chr11-2418312-A-G

Variant names:

• chr11-2418312-A-G
• rs3986599
• NM_014555.4:c.761T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014555.4(TRPM5):​c.761T>C​(p.Val254Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.688 in 1,568,652 control chromosomes in the GnomAD database, including 376,855 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.76 (44998 hom., cov: 31)
  • Exomes 𝑓: 0.68 (331857 hom.)
• Consequence: TRPM5 NM_014555.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• Publications: 23 publications found

Genes affected

TRPM5 (HGNC:14323): (transient receptor potential cation channel subfamily M member 5) This gene encodes a member of the transient receptor potential (TRP) protein family, which is a diverse group of proteins with structural features typical of ion channels. This protein plays an important role in taste transduction, and has characteristics of a calcium-activated, non-selective cation channel that carries Na+, K+, and Cs+ ions equally well, but not Ca(2+) ions. It is activated by lower concentrations of intracellular Ca(2+), and inhibited by higher concentrations. It is also a highly temperature-sensitive, heat activated channel showing a steep increase of inward currents at temperatures between 15 and 35 degrees Celsius. This gene is located within the Beckwith-Wiedemann syndrome critical region-1 on chromosome 11p15.5, and has been shown to be imprinted, with exclusive expression from the paternal allele. [provided by RefSeq, Oct 2010]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=2.197801E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM5	NM_014555.4	c.761T>C	p.Val254Ala	missense_variant	Exon 11 of 29	ENST00000696290.1	NP_055370.1
TRPM5	XM_017017628.2	c.815T>C	p.Val272Ala	missense_variant	Exon 8 of 26		XP_016873117.1
TRPM5	XM_047426858.1	c.815T>C	p.Val272Ala	missense_variant	Exon 8 of 26		XP_047282814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM5	ENST00000696290.1	c.761T>C	p.Val254Ala	missense_variant	Exon 11 of 29		NM_014555.4	ENSP00000512529.1
TRPM5	ENST00000533060.5	c.761T>C	p.Val254Ala	missense_variant	Exon 6 of 24	1		ENSP00000434121.1
TRPM5	ENST00000528453.1	c.761T>C	p.Val254Ala	missense_variant	Exon 6 of 24	1		ENSP00000436809.1
TRPM5	ENST00000533881.5	c.743T>C	p.Val248Ala	missense_variant	Exon 6 of 24	1		ENSP00000434383.1

Frequencies

GnomAD3 genomes AF: 0.760 AC: 115289 AN: 151730 Hom.: 44939 Cov.: 31

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.898

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.768

GnomAD2 exomes AF: 0.738 AC: 133451 AN: 180908 AF XY: 0.732

Gnomad AFR exome AF: 0.937

Gnomad AMR exome AF: 0.858

Gnomad ASJ exome AF: 0.659

Gnomad EAS exome AF: 0.896

Gnomad FIN exome AF: 0.649

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.723

GnomAD4 exome AF: 0.681 AC: 964449 AN: 1416804 Hom.: 331857 Cov.: 71 AF XY: 0.682 AC XY: 477741 AN XY: 700460

African (AFR) AF: 0.940 AC: 30504 AN: 32466

American (AMR) AF: 0.853 AC: 32548 AN: 38176

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 16679 AN: 25394

East Asian (EAS) AF: 0.892 AC: 33247 AN: 37286

South Asian (SAS) AF: 0.771 AC: 62482 AN: 81038

European-Finnish (FIN) AF: 0.653 AC: 31852 AN: 48808

Middle Eastern (MID) AF: 0.761 AC: 4339 AN: 5704

European-Non Finnish (NFE) AF: 0.653 AC: 711283 AN: 1089322

Other (OTH) AF: 0.708 AC: 41515 AN: 58610

GnomAD4 genome AF: 0.760 AC: 115408 AN: 151848 Hom.: 44998 Cov.: 31 AF XY: 0.761 AC XY: 56460 AN XY: 74174

African (AFR) AF: 0.929 AC: 38545 AN: 41488

American (AMR) AF: 0.813 AC: 12414 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2275 AN: 3464

East Asian (EAS) AF: 0.898 AC: 4545 AN: 5060

South Asian (SAS) AF: 0.786 AC: 3783 AN: 4810

European-Finnish (FIN) AF: 0.656 AC: 6901 AN: 10516

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44662 AN: 67926

Other (OTH) AF: 0.767 AC: 1618 AN: 2110

Alfa AF: 0.694 Hom.: 62922

Bravo AF: 0.780

TwinsUK AF: 0.634 AC: 2352

ALSPAC AF: 0.660 AC: 2542

ESP6500AA AF: 0.924 AC: 4013

ESP6500EA AF: 0.663 AC: 5658

ExAC AF: 0.694 AC: 78778

Asia WGS AF: 0.835 AC: 2906 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.14
DEOGEN2	Benign	0.12	.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.015	T;T;T;T
MetaRNN	Benign	0.0000022	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.6	.;N;.;.
PhyloP100		2.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	2.5	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.049, 0.027, 0.046
MPC		0.11
ClinPred		0.0017	T
GERP RS		2.5
Varity_R		0.034
gMVP		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3986599; hg19: chr11-2439542; COSMIC: COSV50155045;