rs1555750883

Positions:

• chr19-49166154-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017636.4(TRPM4):​c.206A>G​(p.Glu69Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRPM4 NM_017636.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.36

Genes affected

TRPM4 (HGNC:17993): (transient receptor potential cation channel subfamily M member 4) The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM4	NM_017636.4	c.206A>G	p.Glu69Gly	missense_variant	3/25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10	c.206A>G	p.Glu69Gly	missense_variant	3/25	1	NM_017636.4	ENSP00000252826	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2017

- -

Progressive familial heart block type IB Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 69 of the TRPM4 protein (p.Glu69Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TRPM4-related conditions. ClinVar contains an entry for this variant (Variation ID: 521277). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.0	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.0	.;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0090	.;D;D
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		1.0	.;D;D
Vest4		0.64, 0.64
MutPred		0.26		Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);
MVP		0.92
MPC		0.92
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.46
gMVP		0.63

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: rs1555750883; hg19: chr19-49669411;