19-49196460-A-T

Variant summary

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

The NM_017636.4(TRPM4):​c.2231A>T​(p.Lys744Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,548,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.446
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 (MetaRNN=0.02162236).
BP6
Variant 19-49196460-A-T is Benign according to our data. Variant chr19-49196460-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 329862.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TRPM4NM_017636.4 linkuse as main transcriptc.2231A>T p.Lys744Met missense_variant 17/25 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.2231A>T p.Lys744Met missense_variant 17/251 NM_017636.4 ENSP00000252826.4 Q8TD43-1

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152052
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000966
Gnomad SAS
AF:
0.000831
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000100
AC:
15
AN:
149694
Hom.:
0
AF XY:
0.0000973
AC XY:
8
AN XY:
82216
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000923
Gnomad SAS exome
AF:
0.000184
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000279
AC:
39
AN:
1395990
Hom.:
0
Cov.:
32
AF XY:
0.0000290
AC XY:
20
AN XY:
689568
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000519
Gnomad4 SAS exome
AF:
0.000191
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.24e-7
Gnomad4 OTH exome
AF:
0.0000690
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152168
Hom.:
0
Cov.:
31
AF XY:
0.0000806
AC XY:
6
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000968
Gnomad4 SAS
AF:
0.000832
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000567
ExAC
AF:
0.0000726
AC:
8
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Progressive familial heart block type IB Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 22, 2022- -
TRPM4-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 22, 2022This 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
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 12, 2024This 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
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
17
DANN
Benign
0.90
DEOGEN2
Benign
0.17
T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.59
T
M_CAP
Benign
0.078
D
MetaRNN
Benign
0.022
T
MetaSVM
Benign
-0.89
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-0.84
N
REVEL
Benign
0.19
Sift
Benign
0.061
T
Sift4G
Uncertain
0.039
D
Polyphen
0.99
D
Vest4
0.37
MutPred
0.33
Loss of ubiquitination at K744 (P = 1e-04);
MVP
0.58
MPC
0.56
ClinPred
0.048
T
GERP RS
2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.074
gMVP
0.58

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.

Other links and lift over

dbSNP: rs569301210; hg19: chr19-49699717; API