rs182549235

Positions:

• chr15-31026219-C-G
• chr15-31026219-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001252024.2(TRPM1):​c.3549G>C​(p.Gln1183His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,612,564 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q1183Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (26 hom.)
• Consequence: TRPM1 NM_001252024.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.725

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]

LOC105370752 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0092971325).
• BP6: Variant 15-31026219-C-G is Benign according to our data. Variant chr15-31026219-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 167747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-31026219-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00347 (529/152380) while in subpopulation NFE AF= 0.0055 (374/68044). AF 95% confidence interval is 0.00504. There are 2 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM1	NM_001252024.2	c.3549G>C	p.Gln1183His	missense_variant	27/28	ENST00000256552.11
LOC105370752	XR_932055.2	n.32C>G		non_coding_transcript_exon_variant	1/4
TRPM1	NM_001252020.2	c.3600G>C	p.Gln1200His	missense_variant	26/27
TRPM1	NM_002420.6	c.3483G>C	p.Gln1161His	missense_variant	26/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM1	ENST00000256552.11	c.3549G>C	p.Gln1183His	missense_variant	27/28	1	NM_001252024.2	P4
	ENST00000665655.1	n.72-746C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 529 AN: 152262 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00364 AC: 902 AN: 248122 Hom.: 3 AF XY: 0.00379 AC XY: 511 AN XY: 134734

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00636

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.00123

Gnomad NFE exome AF: 0.00542

Gnomad OTH exome AF: 0.00364

GnomAD4 exome AF: 0.00516 AC: 7540 AN: 1460184 Hom.: 26 Cov.: 32 AF XY: 0.00503 AC XY: 3655 AN XY: 726504

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.00627

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00337

Gnomad4 FIN exome AF: 0.00143

Gnomad4 NFE exome AF: 0.00591

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152380 Hom.: 2 Cov.: 33 AF XY: 0.00329 AC XY: 245 AN XY: 74520

Gnomad4 AFR AF: 0.000841

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00165

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00550

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00487 Hom.: 1

Bravo AF: 0.00318

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00118 AC: 5

ESP6500EA AF: 0.00424 AC: 36

ExAC AF: 0.00368 AC: 446

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00539

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TRPM1: BP4, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 28, 2015

- -

Congenital stationary night blindness 1C Benign:1

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;.;T;T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0093	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D;D;D;.;D;D
REVEL	Benign	0.17
Sift	Benign	0.037	D;D;D;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		0.79	P;.;.;.;.;.
Vest4		0.44
MutPred		0.32		Loss of helix (P = 0.0558);.;.;.;.;Loss of helix (P = 0.0558);
MVP		0.39
MPC		0.24
ClinPred		0.048	T
GERP RS		-0.35
Varity_R		0.33
gMVP		0.56

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: rs182549235; hg19: chr15-31318422;