15-31042159-C-T

Variant names:

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.1879G>A(p.Val627Met) variant causes a missense change. The variant allele was found at a frequency of 0.0304 in 1,614,128 control chromosomes in the GnomAD database, including 860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V627L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.023 ( 70 hom., cov: 32)

Exomes 𝑓: 0.031 ( 790 hom. )

Consequence

TRPM1
NM_001252024.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.83

Publications

20 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=0.004008323).

BP6

Variant 15-31042159-C-T is Benign according to our data. Variant chr15-31042159-C-T is described in ClinVar as Benign. ClinVar VariationId is 315519.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 = 0.0234 (3562/152306) while in subpopulation NFE AF = 0.0367 (2494/68016). AF 95% confidence interval is 0.0355. There are 70 homozygotes in GnomAd4. There are 1619 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 70 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TRPM1	NM_001252024.2 link	c.1879G>A	p.Val627Met	missense_variant	Exon 17 of 28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_001252020.2 link	c.1930G>A	p.Val644Met	missense_variant	Exon 16 of 27		NP_001238949.1
TRPM1	NM_002420.6 link	c.1813G>A	p.Val605Met	missense_variant	Exon 16 of 27		NP_002411.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11 link	c.1879G>A	p.Val627Met	missense_variant	Exon 17 of 28	1	NM_001252024.2	ENSP00000256552.7

Frequencies

GnomAD3 genomes

AF:

0.0234

AC:

3564

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00642

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0281

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0367

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0242

AC:

6034

AN:

249276

AF XY:

0.0242

show subpopulations

Gnomad AFR exome

AF:

0.00549

Gnomad AMR exome

AF:

0.0187

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0155

Gnomad NFE exome

AF:

0.0374

Gnomad OTH exome

AF:

0.0277

GnomAD4 exome

AF:

0.0311

AC:

45509

AN:

1461822

Hom.:

790

Cov.:

AF XY:

0.0306

AC XY:

22261

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00594

AC:

199

AN:

33480

American (AMR)

AF:

0.0195

AC:

872

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0215

AC:

561

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0139

AC:

1202

AN:

86244

European-Finnish (FIN)

AF:

0.0165

AC:

881

AN:

53414

Middle Eastern (MID)

AF:

0.0184

AC:

106

AN:

5768

European-Non Finnish (NFE)

AF:

0.0360

AC:

40050

AN:

1111968

Other (OTH)

AF:

0.0271

AC:

1638

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

2793

5586

8378

11171

13964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1438

2876

4314

5752

7190

<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:

0.0234

AC:

3562

AN:

152306

Hom.:

Cov.:

AF XY:

0.0217

AC XY:

1619

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00640

AC:

266

AN:

41566

American (AMR)

AF:

0.0281

AC:

430

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.0114

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0118

AC:

125

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0367

AC:

2494

AN:

68016

Other (OTH)

AF:

0.0260

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

180

360

540

720

900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0322

Hom.:

400

Bravo

AF:

0.0232

TwinsUK

AF:

0.0334

AC:

124

ALSPAC

AF:

0.0361

AC:

139

ESP6500AA

AF:

0.00626

AC:

ESP6500EA

AF:

0.0378

AC:

323

ExAC

AF:

0.0248

AC:

3010

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 31, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Congenital stationary night blindness 1C

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.079

T;.;.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

T;T;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.6

L;.;.;.;.

PhyloP100

4.8

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.62

N;N;N;.;N

REVEL

Benign

0.19

Sift

Benign

0.24

T;T;T;.;T

Sift4G

Benign

0.22

T;T;T;T;T

Polyphen

0.99

D;.;.;.;.

Vest4

0.26

MPC

0.24

ClinPred

0.031

GERP RS

3.8

Varity_R

0.13

gMVP

0.41

Mutation Taster

=94/6

polymorphism (auto)

(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