chr19-49168723-G-A

Position:

chr19-49168723-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_017636.4(TRPM4):c.783G>A(p.Lys261=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,591,836 control chromosomes in the GnomAD database, including 376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 49 hom., cov: 30)

Exomes 𝑓: 0.017 ( 327 hom. )

Consequence

TRPM4
NM_017636.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.20

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 19-49168723-G-A is Benign according to our data. Variant chr19-49168723-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 220961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49168723-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.2 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0186 (2826/152094) while in subpopulation SAS AF= 0.036 (173/4806). AF 95% confidence interval is 0.0316. There are 49 homozygotes in gnomad4. There are 1449 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2826 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM4	NM_017636.4 linkuse as main transcript	c.783G>A	p.Lys261=	synonymous_variant	6/25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10 linkuse as main transcript	c.783G>A	p.Lys261=	synonymous_variant	6/25	1	NM_017636.4	ENSP00000252826	P1	Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.0186

AC:

2824

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00708

Gnomad ASJ

AF:

0.0343

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0358

Gnomad FIN

AF:

0.0356

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0208

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0216

AC:

4506

AN:

208910

Hom.:

AF XY:

0.0229

AC XY:

2582

AN XY:

112710

show subpopulations

Gnomad AFR exome

AF:

0.0170

Gnomad AMR exome

AF:

0.00672

Gnomad ASJ exome

AF:

0.0310

Gnomad EAS exome

AF:

0.000192

Gnomad SAS exome

AF:

0.0366

Gnomad FIN exome

AF:

0.0381

Gnomad NFE exome

AF:

0.0223

Gnomad OTH exome

AF:

0.0197

GnomAD4 exome

AF:

0.0170

AC:

24405

AN:

1439742

Hom.:

327

Cov.:

AF XY:

0.0179

AC XY:

12755

AN XY:

714266

show subpopulations

Gnomad4 AFR exome

AF:

0.0139

Gnomad4 AMR exome

AF:

0.00694

Gnomad4 ASJ exome

AF:

0.0299

Gnomad4 EAS exome

AF:

0.0000774

Gnomad4 SAS exome

AF:

0.0351

Gnomad4 FIN exome

AF:

0.0345

Gnomad4 NFE exome

AF:

0.0156

Gnomad4 OTH exome

AF:

0.0161

GnomAD4 genome

AF:

0.0186

AC:

2826

AN:

152094

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1449

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0144

Gnomad4 AMR

AF:

0.00701

Gnomad4 ASJ

AF:

0.0343

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.0360

Gnomad4 FIN

AF:

0.0356

Gnomad4 NFE

AF:

0.0208

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0205

Hom.:

Bravo

AF:

0.0149

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Progressive familial heart block type IB

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

TRPM4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over