rs4779816

Variant names:

• chr15-31076920-A-G
• rs4779816
• ENST00000397795.7:c.2T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-31076920-A-G
• chr15-31076920-A-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_002420.6(TRPM1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 1,606,726 control chromosomes in the GnomAD database, including 544,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55463 hom., cov: 32)
  • Exomes 𝑓: 0.82 (488662 hom.)
• Consequence: TRPM1 NM_002420.6 start_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0460
• Publications: 41 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 71 codons. Genomic position: 31070033. Lost 0.044 part of the original CDS.
• BP6: Variant 15-31076920-A-G is Benign according to our data. Variant chr15-31076920-A-G is described in ClinVar as Benign. ClinVar VariationId is 315540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002420.6. 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.68T>C	p.Met23Thr	missense	Exon 3 of 28	NP_001238953.1	Q7Z4N2-6
	TRPM1	NM_002420.6		c.2T>C	p.Met1?	start_lost	Exon 2 of 27	NP_002411.3
	TRPM1	NM_001252030.2		c.2T>C	p.Met1?	start_lost	Exon 2 of 3	NP_001238959.1	Q7Z4N2-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	ENST00000397795.7	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 2 of 27	ENSP00000380897.2	Q7Z4N2-1
	TRPM1	ENST00000559179.2	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 2 of 3	ENSP00000453851.1	Q7Z4N2-7
	TRPM1	ENST00000256552.11	TSL:1 MANE Select	c.68T>C	p.Met23Thr	missense	Exon 3 of 28	ENSP00000256552.7	Q7Z4N2-6

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129532 AN: 152054 Hom.: 55414 Cov.: 32

Gnomad AFR AF: 0.902

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.874

Gnomad ASJ AF: 0.854

Gnomad EAS AF: 0.977

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.811

Gnomad OTH AF: 0.838

GnomAD2 exomes AF: 0.848 AC: 211620 AN: 249508 AF XY: 0.843

Gnomad AFR exome AF: 0.903

Gnomad AMR exome AF: 0.912

Gnomad ASJ exome AF: 0.851

Gnomad EAS exome AF: 0.984

Gnomad FIN exome AF: 0.811

Gnomad NFE exome AF: 0.803

Gnomad OTH exome AF: 0.843

GnomAD4 exome AF: 0.818 AC: 1190110 AN: 1454554 Hom.: 488662 Cov.: 34 AF XY: 0.819 AC XY: 593133 AN XY: 724094

African (AFR) AF: 0.905 AC: 30153 AN: 33322

American (AMR) AF: 0.908 AC: 40582 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 22090 AN: 26060

East Asian (EAS) AF: 0.970 AC: 38448 AN: 39644

South Asian (SAS) AF: 0.861 AC: 74196 AN: 86142

European-Finnish (FIN) AF: 0.811 AC: 43284 AN: 53372

Middle Eastern (MID) AF: 0.811 AC: 4667 AN: 5754

European-Non Finnish (NFE) AF: 0.802 AC: 886479 AN: 1105396

Other (OTH) AF: 0.835 AC: 50211 AN: 60156

GnomAD4 genome AF: 0.852 AC: 129637 AN: 152172 Hom.: 55463 Cov.: 32 AF XY: 0.854 AC XY: 63508 AN XY: 74368

African (AFR) AF: 0.902 AC: 37482 AN: 41538

American (AMR) AF: 0.874 AC: 13367 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 2959 AN: 3466

East Asian (EAS) AF: 0.977 AC: 5052 AN: 5172

South Asian (SAS) AF: 0.871 AC: 4202 AN: 4822

European-Finnish (FIN) AF: 0.811 AC: 8583 AN: 10578

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.811 AC: 55165 AN: 67988

Other (OTH) AF: 0.837 AC: 1767 AN: 2112

Alfa AF: 0.824 Hom.: 174863

Bravo AF: 0.858

TwinsUK AF: 0.790 AC: 2930

ALSPAC AF: 0.798 AC: 3074

ESP6500AA AF: 0.892 AC: 3317

ESP6500EA AF: 0.801 AC: 6581

ExAC AF: 0.845 AC: 102011

Asia WGS AF: 0.912 AC: 3171 AN: 3478

EpiCase AF: 0.810

EpiControl AF: 0.805

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Congenital stationary night blindness 1C (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.8
DANN	Benign	0.87
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.014	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.046
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.12
Sift	Benign	0.068	T
Sift4G	Benign	0.088	T
Polyphen		0.0	B
Vest4		0.049
MPC		0.24
ClinPred		0.0018	T
GERP RS		2.4
Varity_R		0.066
gMVP		0.13
Mutation Taster		=108/92	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: rs4779816; hg19: chr15-31369123; COSMIC: COSV107213098;