15-31042159-C-T

Variant names:

• chr15-31042159-C-T
• rs17815774
• NM_001252024.2:c.1879G>A

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.1879G>A​(p.Val627Met) variant causes a missense change. The variant allele was found at a frequency of 0.0304 in 1,614,128 control chromosomes in the GnomAD database, including 860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V627L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (70 hom., cov: 32)
  • Exomes 𝑓: 0.031 (790 hom.)
• Consequence: TRPM1 NM_001252024.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.83
• Publications: 20 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=0.004008323).
• BP6: Variant 15-31042159-C-T is Benign according to our data. Variant chr15-31042159-C-T is described in ClinVar as Benign. ClinVar VariationId is 315519.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 = 0.0234 (3562/152306) while in subpopulation NFE AF = 0.0367 (2494/68016). AF 95% confidence interval is 0.0355. There are 70 homozygotes in GnomAd4. There are 1619 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 70 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	NM_001252024.2	MANE Select	c.1879G>A	p.Val627Met	missense	Exon 17 of 28	NP_001238953.1
	TRPM1	NM_001252020.2		c.1930G>A	p.Val644Met	missense	Exon 16 of 27	NP_001238949.1
	TRPM1	NM_002420.6		c.1813G>A	p.Val605Met	missense	Exon 16 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.1879G>A	p.Val627Met	missense	Exon 17 of 28	ENSP00000256552.7
	TRPM1	ENST00000558445.6	TSL:1	c.1930G>A	p.Val644Met	missense	Exon 16 of 27	ENSP00000452946.2
	TRPM1	ENST00000397795.7	TSL:1	c.1813G>A	p.Val605Met	missense	Exon 16 of 27	ENSP00000380897.2

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3564 AN: 152188 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00642

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0281

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0367

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0242 AC: 6034 AN: 249276 AF XY: 0.0242

Gnomad AFR exome AF: 0.00549

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.0374

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0311 AC: 45509 AN: 1461822 Hom.: 790 Cov.: 32 AF XY: 0.0306 AC XY: 22261 AN XY: 727202

African (AFR) AF: 0.00594 AC: 199 AN: 33480

American (AMR) AF: 0.0195 AC: 872 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 561 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0139 AC: 1202 AN: 86244

European-Finnish (FIN) AF: 0.0165 AC: 881 AN: 53414

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5768

European-Non Finnish (NFE) AF: 0.0360 AC: 40050 AN: 1111968

Other (OTH) AF: 0.0271 AC: 1638 AN: 60394

GnomAD4 genome AF: 0.0234 AC: 3562 AN: 152306 Hom.: 70 Cov.: 32 AF XY: 0.0217 AC XY: 1619 AN XY: 74478

African (AFR) AF: 0.00640 AC: 266 AN: 41566

American (AMR) AF: 0.0281 AC: 430 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4824

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10616

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0367 AC: 2494 AN: 68016

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0322 Hom.: 400

Bravo AF: 0.0232

TwinsUK AF: 0.0334 AC: 124

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.00626 AC: 27

ESP6500EA AF: 0.0378 AC: 323

ExAC AF: 0.0248 AC: 3010

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital stationary night blindness 1C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.19
Sift	Benign	0.24	T
Sift4G	Benign	0.22	T
Polyphen		0.99	D
Vest4		0.26
MPC		0.24
ClinPred		0.031	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.41
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: rs17815774; hg19: chr15-31334362; COSMIC: COSV56636581;