11-2415234-C-A

Position:

• chr11-2415234-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014555.4(TRPM5):​c.1366G>T​(p.Ala456Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000563 in 1,420,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A456T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: TRPM5 NM_014555.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.42

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030515373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM5	NM_014555.4	c.1366G>T	p.Ala456Ser	missense_variant	14/29	ENST00000696290.1	NP_055370.1
TRPM5	XM_017017628.2	c.1420G>T	p.Ala474Ser	missense_variant	11/26		XP_016873117.1
TRPM5	XM_047426858.1	c.1420G>T	p.Ala474Ser	missense_variant	11/26		XP_047282814.1
TRPM5	XM_047426859.1	c.217G>T	p.Ala73Ser	missense_variant	2/17		XP_047282815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM5	ENST00000696290.1	c.1366G>T	p.Ala456Ser	missense_variant	14/29		NM_014555.4	ENSP00000512529.1
TRPM5	ENST00000533060.5	c.1366G>T	p.Ala456Ser	missense_variant	9/24	1		ENSP00000434121.1
TRPM5	ENST00000528453.1	c.1366G>T	p.Ala456Ser	missense_variant	9/24	1		ENSP00000436809.1
TRPM5	ENST00000533881.5	c.1348G>T	p.Ala450Ser	missense_variant	9/24	1		ENSP00000434383.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000563 AC: 8 AN: 1420670 Hom.: 0 Cov.: 37 AF XY: 0.00000994 AC XY: 7 AN XY: 704158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000548

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.0020
DANN	Benign	0.38
DEOGEN2	Benign	0.074	.;T;.;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.22	T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.031	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	.;N;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.51	N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.80	T;T;T;T
Sift4G	Benign	0.75	T;T;T;T
Polyphen		0.016, 0.0040	.;B;B;.
Vest4		0.058, 0.067, 0.083
MutPred		0.30		.;Gain of relative solvent accessibility (P = 0.0024);Gain of relative solvent accessibility (P = 0.0024);Gain of relative solvent accessibility (P = 0.0024);
MVP		0.014
MPC		0.082
ClinPred		0.046	T
GERP RS		-6.4
Varity_R		0.047
gMVP		0.17

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: rs34551253; hg19: chr11-2436464;