15-31037741-G-T

Variant names:

• chr15-31037741-G-T
• rs12911350
• NM_001252024.2:c.2541C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001252024.2(TRPM1):​c.2541C>A​(p.Asn847Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N847N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRPM1 NM_001252024.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.470
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	NM_001252024.2	MANE Select	c.2541C>A	p.Asn847Lys	missense	Exon 20 of 28	NP_001238953.1	Q7Z4N2-6
	TRPM1	NM_001252020.2		c.2592C>A	p.Asn864Lys	missense	Exon 19 of 27	NP_001238949.1	Q7Z4N2-5
	TRPM1	NM_002420.6		c.2475C>A	p.Asn825Lys	missense	Exon 19 of 27	NP_002411.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	ENST00000256552.11	TSL:1 MANE Select	c.2541C>A	p.Asn847Lys	missense	Exon 20 of 28	ENSP00000256552.7	Q7Z4N2-6
	TRPM1	ENST00000558445.6	TSL:1	c.2592C>A	p.Asn864Lys	missense	Exon 19 of 27	ENSP00000452946.2	Q7Z4N2-5
	TRPM1	ENST00000397795.7	TSL:1	c.2475C>A	p.Asn825Lys	missense	Exon 19 of 27	ENSP00000380897.2	Q7Z4N2-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.0050
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		-0.47
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.29
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.045	D
Polyphen		0.42	B
Vest4		0.74
MutPred		0.50		Gain of methylation at N825 (P = 0.0075)
MVP		0.23
MPC		0.75
ClinPred		0.99	D
GERP RS		-5.7
Varity_R		0.29
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs12911350; hg19: chr15-31329944;