chr19-49157884-G-C

Variant names:

• chr19-49157884-G-C
• rs2122723185
• NM_017636.4:c.18G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017636.4(TRPM4):​c.18G>C​(p.Lys6Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K6K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRPM4 NM_017636.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18
• Publications: 0 publications found

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]

TRPM4 Gene-Disease associations (from GenCC):

• erythrokeratodermia variabilis et progressiva 6

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• progressive familial heart block type IB

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21546283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM4	NM_017636.4	c.18G>C	p.Lys6Asn	missense_variant	Exon 1 of 25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10	c.18G>C	p.Lys6Asn	missense_variant	Exon 1 of 25	1	NM_017636.4	ENSP00000252826.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

May 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K6N variant (also known as c.18G>C), located in coding exon 1 of the TRPM4 gene, results from a G to C substitution at nucleotide position 18. The lysine at codon 6 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	T;T;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.96	.;L;.;L
PhyloP100		2.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.61	.;N;.;N
REVEL	Benign	0.22
Sift	Benign	0.42	.;T;.;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.33, 0.99	.;B;.;D
Vest4		0.31, 0.17, 0.26
MutPred		0.28		Loss of methylation at K6 (P = 0.0031);Loss of methylation at K6 (P = 0.0031);Loss of methylation at K6 (P = 0.0031);Loss of methylation at K6 (P = 0.0031);
MVP		0.81
MPC		1.1
ClinPred		0.94	D
GERP RS		3.2
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.36
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs2122723185; hg19: chr19-49661141;