rs878855029

chr19-49182771-CCAAAGCCCCAGCCCTAAAAGGGGGAGCTGCGGAGCT-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_017636.4(TRPM4):c.1459_1494del(p.Lys487_Leu498del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,614,016 control chromosomes in the GnomAD database, including 138 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T486T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0073 (5 hom., cov: 32)
  • Exomes 𝑓: 0.012 (133 hom.)
• Consequence: TRPM4 NM_017636.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.85

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_017636.4.
• BP6: Variant 19-49182771-CCAAAGCCCCAGCCCTAAAAGGGGGAGCTGCGGAGCT-C is Benign according to our data. Variant chr19-49182771-CCAAAGCCCCAGCCCTAAAAGGGGGAGCTGCGGAGCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241175.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=5, Uncertain_significance=1}. Variant chr19-49182771-CCAAAGCCCCAGCCCTAAAAGGGGGAGCTGCGGAGCT-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00729 (1110/152360) while in subpopulation NFE AF= 0.012 (816/68034). AF 95% confidence interval is 0.0113. There are 5 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1111 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM4	NM_017636.4	c.1459_1494del	p.Lys487_Leu498del	inframe_deletion	11/25	ENST00000252826.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM4	ENST00000252826.10	c.1459_1494del	p.Lys487_Leu498del	inframe_deletion	11/25	1	NM_017636.4	P1

Frequencies

GnomAD3 genomes AF: 0.00730 AC: 1111 AN: 152242 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00971

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00784 AC: 1944 AN: 247918 Hom.: 10 AF XY: 0.00792 AC XY: 1066 AN XY: 134562

Gnomad AFR exome AF: 0.00177

Gnomad AMR exome AF: 0.00602

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00608

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0117 AC: 17131 AN: 1461656 Hom.: 133 AF XY: 0.0116 AC XY: 8425 AN XY: 727134

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00657

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00665

Gnomad4 FIN exome AF: 0.00456

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00729 AC: 1110 AN: 152360 Hom.: 5 Cov.: 32 AF XY: 0.00695 AC XY: 518 AN XY: 74508

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00972

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.0108 Hom.: 3

Bravo AF: 0.00688

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2019	- -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Nov 16, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 21, 2023

Variant summary: TRPM4 c.1459_1494del36 (p.Lys487_Leu498del) results in an in-frame deletion that is predicted to remove twelve amino acids from the encoded protein. The variant allele was found at a frequency of 0.0078 in 247918 control chromosomes, predominantly at a frequency of 0.011 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4399.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in TRPM4 causing Progressive Familial Heart Block Type 1B phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1459_1494del36 has been reported in the literature as a polymorphism, and in a patient with a pathogenic variant explaining their phenotype (Syam_2016, Neubauer_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27207958, 33895855). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: five classified the variant as likely benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Sep 08, 2017

- -

TRPM4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2020

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). -

Progressive familial heart block type IB Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2016

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878855029; hg19: chr19-49686028;