rs17227996

Variant names:

• chr15-31002948-T-G
• rs17227996
• NM_001252024.2:c.3752A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001252024.2(TRPM1):​c.3752A>C​(p.Asn1251Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,601,860 control chromosomes in the GnomAD database, including 2,567 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 0.041 (194 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2373 hom.)
• Consequence: TRPM1 NM_001252024.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.611
• Publications: 17 publications found

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

ENSG00000259720 (HGNC:58477):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012834966).
• BP6: Variant 15-31002948-T-G is Benign according to our data. Variant chr15-31002948-T-G is described in ClinVar as Benign. ClinVar VariationId is 315501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM1	NM_001252024.2	c.3752A>C	p.Asn1251Thr	missense_variant	Exon 28 of 28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_001252020.2	c.3803A>C	p.Asn1268Thr	missense_variant	Exon 27 of 27		NP_001238949.1
TRPM1	NM_002420.6	c.3686A>C	p.Asn1229Thr	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	c.3752A>C	p.Asn1251Thr	missense_variant	Exon 28 of 28	1	NM_001252024.2	ENSP00000256552.7

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6180 AN: 152184 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0774

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0611

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0408 AC: 9929 AN: 243126 AF XY: 0.0409

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0303

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.0789

Gnomad NFE exome AF: 0.0595

Gnomad OTH exome AF: 0.0431

GnomAD4 exome AF: 0.0531 AC: 77003 AN: 1449558 Hom.: 2373 Cov.: 34 AF XY: 0.0518 AC XY: 37288 AN XY: 719390

African (AFR) AF: 0.00943 AC: 311 AN: 32978

American (AMR) AF: 0.0225 AC: 976 AN: 43442

Ashkenazi Jewish (ASJ) AF: 0.0316 AC: 810 AN: 25656

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39482

South Asian (SAS) AF: 0.00638 AC: 541 AN: 84802

European-Finnish (FIN) AF: 0.0788 AC: 4187 AN: 53122

Middle Eastern (MID) AF: 0.0271 AC: 155 AN: 5712

European-Non Finnish (NFE) AF: 0.0610 AC: 67376 AN: 1104588

Other (OTH) AF: 0.0442 AC: 2643 AN: 59776

GnomAD4 genome AF: 0.0406 AC: 6180 AN: 152302 Hom.: 194 Cov.: 32 AF XY: 0.0397 AC XY: 2959 AN XY: 74462

African (AFR) AF: 0.0112 AC: 464 AN: 41568

American (AMR) AF: 0.0304 AC: 465 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4826

European-Finnish (FIN) AF: 0.0774 AC: 821 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0611 AC: 4153 AN: 68016

Other (OTH) AF: 0.0302 AC: 64 AN: 2116

Alfa AF: 0.0505 Hom.: 749

Bravo AF: 0.0364

TwinsUK AF: 0.0596 AC: 221

ALSPAC AF: 0.0646 AC: 249

ESP6500AA AF: 0.0110 AC: 43

ESP6500EA AF: 0.0607 AC: 503

ExAC AF: 0.0397 AC: 4793

Asia WGS AF: 0.00520 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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

- -

Apr 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital stationary night blindness 1C Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.053	T;.;.;T;T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.70	T;T;T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.
PhyloP100		0.61
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.22	N;N;N;.;N;N
REVEL	Benign	0.034
Sift	Benign	0.69	T;T;T;.;T;T
Sift4G	Benign	0.67	T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.054
MPC		0.21
ClinPred		0.0047	T
GERP RS		2.8
Varity_R		0.053
gMVP		0.20
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17227996; hg19: chr15-31295151;