rs56355369

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_017636.4(TRPM4):c.1682A>C(p.Asp561Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00589 in 1,614,014 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D561E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 52 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11

Conservation

PhyloP100: 1.50

Publications

19 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: Labcorp Genetics (formerly Invitae), G2P, 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013607472).

BP6

Variant 19-49183151-A-C is Benign according to our data. Variant chr19-49183151-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 180563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 558 AD gene.

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	UniProt
TRPM4	NM_017636.4	MANE Select	c.1682A>C	p.Asp561Ala	missense	Exon 12 of 25	NP_060106.2
TRPM4	NM_001321281.2		c.1337A>C	p.Asp446Ala	missense	Exon 10 of 23	NP_001308210.1
TRPM4	NM_001195227.2		c.1682A>C	p.Asp561Ala	missense	Exon 12 of 24	NP_001182156.1	Q8TD43-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.1682A>C	p.Asp561Ala	missense	Exon 12 of 25	ENSP00000252826.4	Q8TD43-1
TRPM4	ENST00000427978.6	TSL:1	c.1682A>C	p.Asp561Ala	missense	Exon 12 of 24	ENSP00000407492.1	Q8TD43-3
TRPM4	ENST00000595519.5	TSL:1	n.*1092A>C		non_coding_transcript_exon	Exon 10 of 23	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes

AF:

0.00367

AC:

558

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00666

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00357

AC:

896

AN:

251312

AF XY:

0.00381

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00245

Gnomad NFE exome

AF:

0.00613

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00612

AC:

8941

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00595

AC XY:

4328

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33476

American (AMR)

AF:

0.00152

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00209

AC:

180

AN:

86248

European-Finnish (FIN)

AF:

0.00260

AC:

139

AN:

53406

Middle Eastern (MID)

AF:

0.000879

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00733

AC:

8152

AN:

1112010

Other (OTH)

AF:

0.00606

AC:

366

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

525

1050

1576

2101

2626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

314

628

942

1256

1570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00367

AC:

558

AN:

152240

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

244

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41548

American (AMR)

AF:

0.00183

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00666

AC:

453

AN:

67996

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00495

Hom.:

Bravo

AF:

0.00351

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00412

AC:

500

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00573

EpiControl

AF:

0.00581

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Progressive familial heart block type IB (2)

Arrhythmogenic right ventricular cardiomyopathy;C0878544:Cardiomyopathy (1)

Cardiovascular phenotype (1)

TRPM4-related disorder (1)

Ventricular fibrillation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

Eigen

Benign

0.074

Eigen_PC

Benign

0.0022

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.014

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.6

PhyloP100

1.5

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.49

Sift

Uncertain

0.0090

Sift4G

Benign

0.063

Polyphen

0.084

Vest4

0.47

MVP

0.94

MPC

1.1

ClinPred

0.066

GERP RS

4.0

Varity_R

0.48

gMVP

0.59

Mutation Taster

=84/16

polymorphism

(source)

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over