Genetic Variant NM_017636.4:c.2214G>C (chr19-49196443-G-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_017636.4(TRPM4):c.2214G>C(p.Thr738Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T738T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

TRPM4
NM_017636.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.87

Publications

0 publications found

Variant links:

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

TRPM4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP7

Synonymous conserved (PhyloP=-1.87 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM4	NM_017636.4	MANE Select	c.2214G>C	p.Thr738Thr	synonymous	Exon 17 of 25	NP_060106.2
TRPM4	NM_001321281.2		c.1869G>C	p.Thr623Thr	synonymous	Exon 15 of 23	NP_001308210.1
TRPM4	NM_001321283.2		c.1692G>C	p.Thr564Thr	synonymous	Exon 15 of 23	NP_001308212.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.2214G>C	p.Thr738Thr	synonymous	Exon 17 of 25	ENSP00000252826.4
TRPM4	ENST00000595519.5	TSL:1	n.*1624G>C		non_coding_transcript_exon	Exon 15 of 23	ENSP00000469893.1
TRPM4	ENST00000598502.5	TSL:1	n.*1327G>C		non_coding_transcript_exon	Exon 16 of 24	ENSP00000470229.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.20e-7

AC:

AN:

1388214

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

685174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31642

American (AMR)

AF:

0.00

AC:

AN:

33512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23976

East Asian (EAS)

AF:

0.00

AC:

AN:

36278

South Asian (SAS)

AF:

0.00

AC:

AN:

77290

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078416

Other (OTH)

AF:

0.00

AC:

AN:

57562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.15

(source)

DANN

Benign

0.57

PhyloP100

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over