chr2-105363452-A-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001318895.3(FHL2):c.521T>A(p.Val174Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,609,438 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V174A) has been classified as Uncertain significance.
Frequency
Consequence
NM_001318895.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FHL2 | NM_001318895.3 | c.521T>A | p.Val174Asp | missense_variant | 6/7 | ENST00000530340.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FHL2 | ENST00000530340.6 | c.521T>A | p.Val174Asp | missense_variant | 6/7 | 1 | NM_001318895.3 | P1 | |
ENST00000457290.2 | n.40+375A>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000330 AC: 5AN: 151730Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000208 AC: 5AN: 240304Hom.: 0 AF XY: 0.0000385 AC XY: 5AN XY: 129818
GnomAD4 exome AF: 0.0000350 AC: 51AN: 1457708Hom.: 0 Cov.: 32 AF XY: 0.0000414 AC XY: 30AN XY: 724702
GnomAD4 genome AF: 0.0000330 AC: 5AN: 151730Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3AN XY: 74092
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 31, 2022 | The c.521T>A (p.V174D) alteration is located in exon 7 (coding exon 4) of the FHL2 gene. This alteration results from a T to A substitution at nucleotide position 521, causing the valine (V) at amino acid position 174 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 24, 2023 | This variant is present in population databases (rs144442113, gnomAD 0.004%). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 174 of the FHL2 protein (p.Val174Asp). This variant has not been reported in the literature in individuals affected with FHL2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FHL2 protein function. ClinVar contains an entry for this variant (Variation ID: 940440). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at