rs111783027

Positions:

• chr19-49167955-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017636.4(TRPM4):​c.306T>G​(p.Val102Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,566,752 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (37 hom.)
• Consequence: TRPM4 NM_017636.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.436

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-49167955-T-G is Benign according to our data. Variant chr19-49167955-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 220960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49167955-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.436 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00663 (987/148794) while in subpopulation SAS AF= 0.0109 (50/4582). AF 95% confidence interval is 0.0085. There are 14 homozygotes in gnomad4. There are 497 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 987 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM4	NM_017636.4	c.306T>G	p.Val102Val	synonymous_variant	4/25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10	c.306T>G	p.Val102Val	synonymous_variant	4/25	1	NM_017636.4	ENSP00000252826.4

Frequencies

GnomAD3 genomes AF: 0.00663 AC: 986 AN: 148680 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00257

Gnomad ASJ AF: 0.0123

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0109

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.00755

Gnomad OTH AF: 0.00340

GnomAD3 exomes AF: 0.0000786 AC: 19 AN: 241648 Hom.: 0 AF XY: 0.0000767 AC XY: 10 AN XY: 130298

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000210

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000347

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.00163 AC: 2314 AN: 1417958 Hom.: 37 Cov.: 34 AF XY: 0.00187 AC XY: 1315 AN XY: 704414

Gnomad4 AFR exome AF: 0.00223

Gnomad4 AMR exome AF: 0.000972

Gnomad4 ASJ exome AF: 0.00507

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00432

Gnomad4 FIN exome AF: 0.00530

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00663 AC: 987 AN: 148794 Hom.: 14 Cov.: 32 AF XY: 0.00684 AC XY: 497 AN XY: 72638

Gnomad4 AFR AF: 0.00565

Gnomad4 AMR AF: 0.00257

Gnomad4 ASJ AF: 0.0123

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0109

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.00755

Gnomad4 OTH AF: 0.00337

Alfa AF: 0.0160 Hom.: 8

Bravo AF: 0.0145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2023	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	TRPM4: BP4, BP7, BS2 -

Progressive familial heart block type IB Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

TRPM4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2019

This variant is classified as likely 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

Dec 15, 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	-0.50
CADD	Benign	6.4
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs111783027; hg19: chr19-49671212; COSMIC: COSV53269460; COSMIC: COSV53269460;