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: 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: 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

Sel.	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	Q7Z4N2-6
	TRPM1	NM_001252020.2		c.3600G>C	p.Gln1200His	missense	Exon 26 of 27	NP_001238949.1	Q7Z4N2-5
	TRPM1	NM_002420.6		c.3483G>C	p.Gln1161His	missense	Exon 26 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.3549G>C	p.Gln1183His	missense	Exon 27 of 28	ENSP00000256552.7	Q7Z4N2-6
	TRPM1	ENST00000558445.6	TSL:1	c.3600G>C	p.Gln1200His	missense	Exon 26 of 27	ENSP00000452946.2	Q7Z4N2-5
	TRPM1	ENST00000397795.7	TSL:1	c.3483G>C	p.Gln1161His	missense	Exon 26 of 27	ENSP00000380897.2	Q7Z4N2-1

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Congenital stationary night blindness 1C (1)
-	-	1	not specified (1)

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;