NM_001252024.2:c.4249G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001252024.2(TRPM1):c.4249G>A(p.Val1417Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0651 in 1,614,154 control chromosomes in the GnomAD database, including 4,382 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 0.057 ( 374 hom., cov: 33)

Exomes 𝑓: 0.066 ( 4008 hom. )

Consequence

TRPM1
NM_001252024.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.677

Publications

26 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=0.0011872351).

BP6

Variant 15-31002451-C-T is Benign according to our data. Variant chr15-31002451-C-T is described in ClinVar as Benign. ClinVar VariationId is 315496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM1	NM_001252024.2 link	c.4249G>A	p.Val1417Ile	missense_variant	Exon 28 of 28	ENST00000256552.11	NP_001238953.1	Q7Z4N2-6
TRPM1	NM_001252020.2 link	c.4300G>A	p.Val1434Ile	missense_variant	Exon 27 of 27		NP_001238949.1	Q7Z4N2-5
TRPM1	NM_002420.6 link	c.4183G>A	p.Val1395Ile	missense_variant	Exon 27 of 27		NP_002411.3	Q7Z4N2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11 link	c.4249G>A	p.Val1417Ile	missense_variant	Exon 28 of 28	1	NM_001252024.2	ENSP00000256552.7		Q7Z4N2-6

Frequencies

GnomAD3 genomes

AF:

0.0573

AC:

8716

AN:

152164

Hom.:

369

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0239

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.108

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.0220

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0562

Gnomad OTH

AF:

0.0695

GnomAD2 exomes

AF:

0.0833

AC:

20796

AN:

249536

AF XY:

0.0828

show subpopulations

Gnomad AFR exome

AF:

0.0216

Gnomad AMR exome

AF:

0.172

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.116

Gnomad FIN exome

AF:

0.0219

Gnomad NFE exome

AF:

0.0593

Gnomad OTH exome

AF:

0.0777

GnomAD4 exome

AF:

0.0659

AC:

96409

AN:

1461872

Hom.:

4008

Cov.:

AF XY:

0.0674

AC XY:

49029

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0228

AC:

762

AN:

33480

American (AMR)

AF:

0.169

AC:

7552

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.116

AC:

3042

AN:

26136

East Asian (EAS)

AF:

0.0850

AC:

3376

AN:

39700

South Asian (SAS)

AF:

0.120

AC:

10314

AN:

86256

European-Finnish (FIN)

AF:

0.0241

AC:

1289

AN:

53418

Middle Eastern (MID)

AF:

0.108

AC:

621

AN:

5768

European-Non Finnish (NFE)

AF:

0.0585

AC:

65044

AN:

1111994

Other (OTH)

AF:

0.0730

AC:

4409

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

6390

12780

19171

25561

31951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2594

5188

7782

10376

12970

<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:

0.0573

AC:

8729

AN:

152282

Hom.:

374

Cov.:

AF XY:

0.0584

AC XY:

4349

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0239

AC:

992

AN:

41574

American (AMR)

AF:

0.131

AC:

1996

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

374

AN:

3464

East Asian (EAS)

AF:

0.109

AC:

563

AN:

5186

South Asian (SAS)

AF:

0.118

AC:

568

AN:

4828

European-Finnish (FIN)

AF:

0.0220

AC:

233

AN:

10612

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0562

AC:

3825

AN:

68014

Other (OTH)

AF:

0.0693

AC:

146

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

421

841

1262

1682

2103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0610

Hom.:

726

Bravo

AF:

0.0630

TwinsUK

AF:

0.0615

AC:

228

ALSPAC

AF:

0.0581

AC:

224

ESP6500AA

AF:

0.0213

AC:

ESP6500EA

AF:

0.0554

AC:

456

ExAC

AF:

0.0786

AC:

9503

Asia WGS

AF:

0.115

AC:

399

AN:

3478

EpiCase

AF:

0.0635

EpiControl

AF:

0.0656

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance: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: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

0.062

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.5

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.067

T;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.84

T;T;T;T

MetaRNN

Benign

0.0012

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.;.

PhyloP100

0.68

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.090

N;N;N;.

REVEL

Benign

0.047

Sift

Benign

0.78

T;T;T;.

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.0020

B;.;.;.

Vest4

0.023

MPC

0.17

ClinPred

0.00035

GERP RS

1.1

Varity_R

0.024

gMVP

0.094

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