rs182549235

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001252024.2(TRPM1):c.3549G>C(p.Gln1183His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,612,564 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q1183Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0052 ( 26 hom. )

Consequence

TRPM1
NM_001252024.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.725

Publications

13 publications found

Variant links:

Genes affected

TRPM1 (HGNC:7146): (transient receptor potential cation channel subfamily M member 1) This gene encodes a member of the transient receptor potential melastatin subfamily of transient receptor potential ion channels. The encoded protein is a calcium permeable cation channel that is expressed in melanocytes and may play a role in melanin synthesis. Specific mutations in this gene are the cause autosomal recessive complete congenital stationary night blindness-1C. The expression of this protein is inversely correlated with melanoma aggressiveness and as such it is used as a prognostic marker for melanoma metastasis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]

TRPM1 Gene-Disease associations (from GenCC):

congenital stationary night blindness 1C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
TRPM1-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
congenital stationary night blindness
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TRPM1 links:

ENSG00000259720 (HGNC:58477):

ENSG00000259720 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0092971325).

BP6

Variant 15-31026219-C-G is Benign according to our data. Variant chr15-31026219-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 167747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00347 (529/152380) while in subpopulation NFE AF = 0.0055 (374/68044). AF 95% confidence interval is 0.00504. There are 2 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TRPM1	NM_001252024.2 link	c.3549G>C	p.Gln1183His	missense_variant	Exon 27 of 28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_001252020.2 link	c.3600G>C	p.Gln1200His	missense_variant	Exon 26 of 27		NP_001238949.1
TRPM1	NM_002420.6 link	c.3483G>C	p.Gln1161His	missense_variant	Exon 26 of 27		NP_002411.3
TRPM1-AS1	XR_932055.2 link	n.32C>G		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11 link	c.3549G>C	p.Gln1183His	missense_variant	Exon 27 of 28	1	NM_001252024.2	ENSP00000256552.7

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

529

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00550

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00364

AC:

902

AN:

248122

AF XY:

0.00379

show subpopulations

Gnomad AFR exome

AF:

0.000710

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00636

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00123

Gnomad NFE exome

AF:

0.00542

Gnomad OTH exome

AF:

0.00364

GnomAD4 exome

AF:

0.00516

AC:

7540

AN:

1460184

Hom.:

Cov.:

AF XY:

0.00503

AC XY:

3655

AN XY:

726504

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33478

American (AMR)

AF:

0.00221

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00627

AC:

164

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00337

AC:

291

AN:

86252

European-Finnish (FIN)

AF:

0.00143

AC:

AN:

51758

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00591

AC:

6567

AN:

1111990

Other (OTH)

AF:

0.00505

AC:

305

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

452

904

1357

1809

2261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

256

512

768

1024

1280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00347

AC:

529

AN:

152380

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.000841

AC:

AN:

41600

American (AMR)

AF:

0.00418

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00779

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00165

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00550

AC:

374

AN:

68044

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00487

Hom.:

Bravo

AF:

0.00318

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00118

AC:

ESP6500EA

AF:

0.00424

AC:

ExAC

AF:

0.00368

AC:

446

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00518

EpiControl

AF:

0.00539

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRPM1: BP4, BS2 -

not specified

Benign:1

Apr 28, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital stationary night blindness 1C

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;.;T;T;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.084

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.0093

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.7

M;.;.;.;.;.

PhyloP100

0.72

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.1

D;D;D;.;D;D

REVEL

Benign

0.17

Sift

Benign

0.037

D;D;D;.;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

0.79

P;.;.;.;.;.

Vest4

0.44

MutPred

0.32

Loss of helix (P = 0.0558);.;.;.;.;Loss of helix (P = 0.0558);

MVP

0.39

MPC

0.24

ClinPred

0.048

GERP RS

-0.35

Varity_R

0.33

gMVP

0.56

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over