chr11-2414726-C-T

Position:

• chr11-2414726-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014555.4(TRPM5):​c.1733G>A​(p.Arg578Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,537,298 control chromosomes in the GnomAD database, including 178,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.48 (17594 hom., cov: 35)
  • Exomes 𝑓: 0.48 (160944 hom.)
• Consequence: TRPM5 NM_014555.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.19

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.4153857E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM5	NM_014555.4	c.1733G>A	p.Arg578Gln	missense_variant	16/29	ENST00000696290.1	NP_055370.1
TRPM5	XM_017017628.2	c.1787G>A	p.Arg596Gln	missense_variant	13/26		XP_016873117.1
TRPM5	XM_047426858.1	c.1787G>A	p.Arg596Gln	missense_variant	13/26		XP_047282814.1
TRPM5	XM_047426859.1	c.584G>A	p.Arg195Gln	missense_variant	4/17		XP_047282815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM5	ENST00000696290.1	c.1733G>A	p.Arg578Gln	missense_variant	16/29		NM_014555.4	ENSP00000512529.1
TRPM5	ENST00000533060.5	c.1733G>A	p.Arg578Gln	missense_variant	11/24	1		ENSP00000434121.1
TRPM5	ENST00000528453.1	c.1733G>A	p.Arg578Gln	missense_variant	11/24	1		ENSP00000436809.1
TRPM5	ENST00000533881.5	c.1715G>A	p.Arg572Gln	missense_variant	11/24	1		ENSP00000434383.1

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72584 AN: 151710 Hom.: 17568 Cov.: 35

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.470

GnomAD3 exomes AF: 0.492 AC: 69284 AN: 140736 Hom.: 17492 AF XY: 0.488 AC XY: 36986 AN XY: 75826

Gnomad AFR exome AF: 0.495

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.344

Gnomad EAS exome AF: 0.679

Gnomad SAS exome AF: 0.474

Gnomad FIN exome AF: 0.462

Gnomad NFE exome AF: 0.471

Gnomad OTH exome AF: 0.482

GnomAD4 exome AF: 0.479 AC: 663889 AN: 1385470 Hom.: 160944 Cov.: 67 AF XY: 0.479 AC XY: 326557 AN XY: 682268

Gnomad4 AFR exome AF: 0.490

Gnomad4 AMR exome AF: 0.539

Gnomad4 ASJ exome AF: 0.344

Gnomad4 EAS exome AF: 0.707

Gnomad4 SAS exome AF: 0.474

Gnomad4 FIN exome AF: 0.466

Gnomad4 NFE exome AF: 0.474

Gnomad4 OTH exome AF: 0.476

GnomAD4 genome AF: 0.479 AC: 72661 AN: 151828 Hom.: 17594 Cov.: 35 AF XY: 0.475 AC XY: 35230 AN XY: 74180

Gnomad4 AFR AF: 0.485

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.667

Gnomad4 SAS AF: 0.494

Gnomad4 FIN AF: 0.452

Gnomad4 NFE AF: 0.470

Gnomad4 OTH AF: 0.470

Alfa AF: 0.462 Hom.: 5980

Bravo AF: 0.485

TwinsUK AF: 0.442 AC: 1640

ALSPAC AF: 0.480 AC: 1848

ESP6500AA AF: 0.451 AC: 1688

ESP6500EA AF: 0.421 AC: 3146

ExAC AF: 0.361 AC: 24651

Asia WGS AF: 0.556 AC: 1932 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.75
DEOGEN2	Benign	0.084	.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.079	T;T;T;T
MetaRNN	Benign	0.0000054	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.1	.;N;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.3	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.75	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.13, 0.047, 0.13
MPC		0.10
ClinPred		0.042	T
GERP RS		3.8
Varity_R		0.075
gMVP		0.059

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

Publications

LitVar

Other links and lift over

dbSNP: rs4929982; hg19: chr11-2435956; COSMIC: COSV50144262;