NM_001252024.2:c.3549G>C

Variant names:

• chr15-31026219-C-G
• rs182549235
• NM_001252024.2:c.3549G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 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=0.0092971325).
• 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 VariationId is 167747.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 = 0.00347 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001252024.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	NM_001252024.2	MANE Select	c.3549G>C	p.Gln1183His	missense	Exon 27 of 28	NP_001238953.1
	TRPM1	NM_001252020.2		c.3600G>C	p.Gln1200His	missense	Exon 26 of 27	NP_001238949.1
	TRPM1	NM_002420.6		c.3483G>C	p.Gln1161His	missense	Exon 26 of 27	NP_002411.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	ENST00000256552.11	TSL:1 MANE Select	c.3549G>C	p.Gln1183His	missense	Exon 27 of 28	ENSP00000256552.7
	TRPM1	ENST00000558445.6	TSL:1	c.3600G>C	p.Gln1200His	missense	Exon 26 of 27	ENSP00000452946.2
	TRPM1	ENST00000397795.7	TSL:1	c.3483G>C	p.Gln1161His	missense	Exon 26 of 27	ENSP00000380897.2

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

GnomAD2 exomes AF: 0.00364 AC: 902 AN: 248122 AF XY: 0.00379

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 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

African (AFR) AF: 0.000747 AC: 25 AN: 33478

American (AMR) AF: 0.00221 AC: 99 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00627 AC: 164 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00337 AC: 291 AN: 86252

European-Finnish (FIN) AF: 0.00143 AC: 74 AN: 51758

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00591 AC: 6567 AN: 1111990

Other (OTH) AF: 0.00505 AC: 305 AN: 60380

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

African (AFR) AF: 0.000841 AC: 35 AN: 41600

American (AMR) AF: 0.00418 AC: 64 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00165 AC: 8 AN: 4834

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00550 AC: 374 AN: 68044

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRPM1: BP4, BS2

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

Apr 28, 2015

Eurofins Ntd Llc (ga)

Significance: Likely 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: Likely 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 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 v4.9

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
Eigen	Benign	0.14
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.72
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.17
Sift	Benign	0.037	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.79	P
Vest4		0.44
MutPred		0.32		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
Mutation Taster		=42/58	disease causing

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: rs182549235; hg19: chr15-31318422;