chr19-49171589-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001321282.2(TRPM4):​c.-684C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,980 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 7 hom., cov: 32)
Exomes 𝑓: 0.0039 ( 15 hom. )

Consequence

TRPM4
NM_001321282.2 5_prime_UTR_premature_start_codon_gain

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -2.22
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
Variant 19-49171589-C-T is Benign according to our data. Variant chr19-49171589-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 386319.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}. Variant chr19-49171589-C-T is described in Lovd as [Benign].
BS2
High AC in GnomAd4 at 560 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TRPM4NM_017636.4 linkuse as main transcriptc.870C>T p.Asn290Asn synonymous_variant 8/25 ENST00000252826.10 NP_060106.2 Q8TD43-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TRPM4ENST00000252826.10 linkuse as main transcriptc.870C>T p.Asn290Asn synonymous_variant 8/251 NM_017636.4 ENSP00000252826.4 Q8TD43-1

Frequencies

GnomAD3 genomes
AF:
0.00368
AC:
560
AN:
152074
Hom.:
7
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000556
Gnomad AMI
AF:
0.0450
Gnomad AMR
AF:
0.00236
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00680
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00543
Gnomad OTH
AF:
0.00431
GnomAD3 exomes
AF:
0.00313
AC:
785
AN:
250494
Hom.:
2
AF XY:
0.00327
AC XY:
444
AN XY:
135590
show subpopulations
Gnomad AFR exome
AF:
0.000376
Gnomad AMR exome
AF:
0.00127
Gnomad ASJ exome
AF:
0.00249
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.00693
Gnomad NFE exome
AF:
0.00466
Gnomad OTH exome
AF:
0.00343
GnomAD4 exome
AF:
0.00391
AC:
5714
AN:
1461788
Hom.:
15
Cov.:
32
AF XY:
0.00378
AC XY:
2748
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.000478
Gnomad4 AMR exome
AF:
0.00121
Gnomad4 ASJ exome
AF:
0.00214
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.000255
Gnomad4 FIN exome
AF:
0.00743
Gnomad4 NFE exome
AF:
0.00445
Gnomad4 OTH exome
AF:
0.00359
GnomAD4 genome
AF:
0.00368
AC:
560
AN:
152192
Hom.:
7
Cov.:
32
AF XY:
0.00364
AC XY:
271
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.000554
Gnomad4 AMR
AF:
0.00236
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00680
Gnomad4 NFE
AF:
0.00544
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.00451
Hom.:
0
Bravo
AF:
0.00328
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00414
EpiControl
AF:
0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2023TRPM4: BP4, BP7, BS2 -
Benign, criteria provided, single submitterclinical testingGeneDxAug 14, 2018- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 22, 2023- -
Progressive familial heart block type IB Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
not specified Benign:2
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 27, 2015This alteration is classified as likely 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
-0.73
CADD
Benign
1.1
DANN
Benign
0.48
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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.

Other links and lift over

dbSNP: rs141997826; hg19: chr19-49674846; COSMIC: COSV99418999; COSMIC: COSV99418999; API