NM_017636.4:c.1744G>T

Variant names:

• chr19-49188641-G-T
• NM_017636.4:c.1744G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_017636.4(TRPM4):​c.1744G>T​(p.Gly582Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G582S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPM4 NM_017636.4 missense, splice_region
• Scores: Splicing: ADA: 0.8473
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-49188641-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM4	NM_017636.4	c.1744G>T	p.Gly582Cys	missense_variant, splice_region_variant	Exon 13 of 25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10	c.1744G>T	p.Gly582Cys	missense_variant, splice_region_variant	Exon 13 of 25	1	NM_017636.4	ENSP00000252826.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive familial heart block type IB Uncertain:1

Nov 28, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with cysteine at codon 582 of the TRPM4 protein (p.Gly582Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TRPM4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	0.35
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;.
Eigen	Benign	0.041
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.85	D;T
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Uncertain	0.54
Sift	Benign	0.12	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.038	B;B
Vest4		0.60
MutPred		0.62		Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.87
MPC		0.34
ClinPred		0.89	D
GERP RS		3.3
Varity_R		0.37
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49691898; COSMIC: COSV105871106; COSMIC: COSV105871106;