chr15-31002499-G-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.4201C>A(p.Pro1401Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,614,038 control chromosomes in the GnomAD database, including 1,212 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 77 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1135 hom. )

Consequence

TRPM1
NM_001252024.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.20

Publications

16 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=0.0022529066).

BP6

Variant 15-31002499-G-T is Benign according to our data. Variant chr15-31002499-G-T is described in ClinVar as Benign. ClinVar VariationId is 315497.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 = 0.0287 (4361/152182) while in subpopulation NFE AF = 0.041 (2788/68006). AF 95% confidence interval is 0.0397. There are 77 homozygotes in GnomAd4. There are 2122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 77 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TRPM1	NM_001252024.2 link	c.4201C>A	p.Pro1401Thr	missense_variant	Exon 28 of 28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_001252020.2 link	c.4252C>A	p.Pro1418Thr	missense_variant	Exon 27 of 27		NP_001238949.1
TRPM1	NM_002420.6 link	c.4135C>A	p.Pro1379Thr	missense_variant	Exon 27 of 27		NP_002411.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11 link	c.4201C>A	p.Pro1401Thr	missense_variant	Exon 28 of 28	1	NM_001252024.2	ENSP00000256552.7

Frequencies

GnomAD3 genomes

AF:

0.0287

AC:

4361

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00667

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0208

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0340

Gnomad FIN

AF:

0.0557

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0410

Gnomad OTH

AF:

0.0344

GnomAD2 exomes

AF:

0.0307

AC:

7662

AN:

249528

AF XY:

0.0322

show subpopulations

Gnomad AFR exome

AF:

0.00743

Gnomad AMR exome

AF:

0.0156

Gnomad ASJ exome

AF:

0.0271

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0546

Gnomad NFE exome

AF:

0.0388

Gnomad OTH exome

AF:

0.0343

GnomAD4 exome

AF:

0.0376

AC:

54951

AN:

1461856

Hom.:

1135

Cov.:

AF XY:

0.0377

AC XY:

27411

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00544

AC:

182

AN:

33480

American (AMR)

AF:

0.0175

AC:

782

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0264

AC:

690

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0315

AC:

2715

AN:

86258

European-Finnish (FIN)

AF:

0.0531

AC:

2836

AN:

53402

Middle Eastern (MID)

AF:

0.0420

AC:

242

AN:

5768

European-Non Finnish (NFE)

AF:

0.0408

AC:

45404

AN:

1111996

Other (OTH)

AF:

0.0348

AC:

2099

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

3508

7015

10523

14030

17538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1656

3312

4968

6624

8280

<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:

0.0287

AC:

4361

AN:

152182

Hom.:

Cov.:

AF XY:

0.0285

AC XY:

2122

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.00665

AC:

276

AN:

41512

American (AMR)

AF:

0.0207

AC:

317

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0342

AC:

165

AN:

4818

European-Finnish (FIN)

AF:

0.0557

AC:

590

AN:

10586

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0410

AC:

2788

AN:

68006

Other (OTH)

AF:

0.0341

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

217

434

650

867

1084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0349

Hom.:

245

Bravo

AF:

0.0254

TwinsUK

AF:

0.0375

AC:

139

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.00756

AC:

ESP6500EA

AF:

0.0407

AC:

333

ExAC

AF:

0.0299

AC:

3611

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.0422

EpiControl

AF:

0.0392

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital stationary night blindness 1C

Benign:2

Jan 12, 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. -

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.0

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.12

T;.;.;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.76

T;T;T;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;.;.;.;.

PhyloP100

1.2

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.2

N;N;N;.;N;N

REVEL

Benign

0.032

Sift

Benign

0.19

T;T;T;.;D;T

Sift4G

Benign

0.085

T;T;T;T;T;T

Polyphen

0.019

B;.;.;.;.;.

Vest4

0.022

MPC

0.23

ClinPred

0.0093

GERP RS

0.51

Varity_R

0.054

gMVP

0.23

Mutation Taster

=100/0

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