chr19-49190719-G-T

Variant names:

• chr19-49190719-G-T
• rs78381230
• NM_017636.4:c.2156G>T

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.2156G>T​(p.Arg719Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. R719W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRPM4 NM_017636.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.323
• 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=0.08945379).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017636.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	NM_017636.4	MANE Select	c.2156G>T	p.Arg719Leu	missense	Exon 16 of 25	NP_060106.2
	TRPM4	NM_001321281.2		c.1811G>T	p.Arg604Leu	missense	Exon 14 of 23	NP_001308210.1
	TRPM4	NM_001195227.2		c.2156G>T	p.Arg719Leu	missense	Exon 16 of 24	NP_001182156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.2156G>T	p.Arg719Leu	missense	Exon 16 of 25	ENSP00000252826.4
	TRPM4	ENST00000427978.6	TSL:1	c.2156G>T	p.Arg719Leu	missense	Exon 16 of 24	ENSP00000407492.1
	TRPM4	ENST00000595519.5	TSL:1	n.*1566G>T		non_coding_transcript_exon	Exon 14 of 23	ENSP00000469893.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.51
DANN	Benign	0.87
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.32
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.062	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.30		Gain of helix (P = 0.0093)
MVP		0.42
MPC		0.35
ClinPred		0.032	T
GERP RS		0.41
Varity_R		0.050
gMVP		0.24
Mutation Taster		=76/24	polymorphism

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: rs78381230; hg19: chr19-49693976; COSMIC: COSV53262381;