rs12913672

chr15-31038110-A-Gchr15-31038110-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001252024.2(TRPM1):c.2373T>C(p.Tyr791=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,592 control chromosomes in the GnomAD database, including 46,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4502 hom., cov: 33)
  • Exomes 𝑓: 0.23 (42039 hom.)
• Consequence: TRPM1 NM_001252024.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.988

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-31038110-A-G is Benign according to our data. Variant chr15-31038110-A-G is described in ClinVar as [Benign]. Clinvar id is 315512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM1	NM_001252024.2	c.2373T>C	p.Tyr791=	synonymous_variant	19/28	ENST00000256552.11
TRPM1	NM_001252020.2	c.2424T>C	p.Tyr808=	synonymous_variant	18/27
TRPM1	NM_002420.6	c.2307T>C	p.Tyr769=	synonymous_variant	18/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM1	ENST00000256552.11	c.2373T>C	p.Tyr791=	synonymous_variant	19/28	1	NM_001252024.2	P4

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36309 AN: 152022 Hom.: 4496 Cov.: 33

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.253

GnomAD3 exomes AF: 0.226 AC: 56427 AN: 249138 Hom.: 7130 AF XY: 0.226 AC XY: 30483 AN XY: 135162

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.00863

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.235 AC: 343354 AN: 1461452 Hom.: 42039 Cov.: 36 AF XY: 0.233 AC XY: 169192 AN XY: 727020

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.0220

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.259

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.239 AC: 36361 AN: 152140 Hom.: 4502 Cov.: 33 AF XY: 0.238 AC XY: 17703 AN XY: 74376

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.251

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.253

Alfa AF: 0.248 Hom.: 9679

Bravo AF: 0.244

Asia WGS AF: 0.0980 AC: 343 AN: 3478

EpiCase AF: 0.252

EpiControl AF: 0.259

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Congenital stationary night blindness 1C Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.56
Dann	Benign	0.55

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

LitVar

Other links and lift over

dbSNP: rs12913672; hg19: chr15-31330313;