rs397517959

Variant names:

• chr2-105367680-G-A
• rs397517959
• NM_001318895.3:c.391C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-105367680-G-A
• chr2-105367680-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001318895.3(FHL2):​c.391C>T​(p.Arg131Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FHL2 NM_001318895.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.79

Genes affected

FHL2 (HGNC:3703): (four and a half LIM domains 2) This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. This protein is thought to have a role in the assembly of extracellular membranes. Also, this gene is down-regulated during transformation of normal myoblasts to rhabdomyosarcoma cells and the encoded protein may function as a link between presenilin-2 and an intracellular signaling pathway. Multiple alternatively spliced variants encoding different isoforms have been identified. [provided by RefSeq, Jan 2016]

ENSG00000238273 (HGNC:):

C2orf49 (HGNC:28772): (chromosome 2 open reading frame 49) Predicted to be involved in embryonic morphogenesis. Located in nucleus. Part of tRNA-splicing ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL2	NM_001318895.3	c.391C>T	p.Arg131Cys	missense_variant	Exon 5 of 7	ENST00000530340.6	NP_001305824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL2	ENST00000530340.6	c.391C>T	p.Arg131Cys	missense_variant	Exon 5 of 7	1	NM_001318895.3	ENSP00000433567.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 03, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg131Cys variant in FHL2 has not been reported in the literature nor previo usly identified by our laboratory. In addition, it has not been identified in la rge and broad populations by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS). Computational analyses (biochemical amino acid properties, c onservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impac t the protein, though this information is not predictive enough to determine pat hogenicity. In summary, this low frequency and computational predictions are con sistent with a disease-causing role, but insufficient to establish this with con fidence. Additional studies are needed to fully assess the clinical significance of the Arg131Cys variant. -

Primary dilated cardiomyopathy Uncertain:1

Aug 12, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 48323). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 131 of the FHL2 protein (p.Arg131Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	.;.;D;D;D;D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	.;.;.;.;.;.;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	2.0	.;.;M;M;M;M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	.;N;N;N;N;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.018	.;D;T;T;T;T;T
Sift4G	Benign	0.071	T;D;T;T;T;T;T
Polyphen		0.99	.;.;D;D;D;D;D
Vest4		0.58
MutPred		0.39		.;.;Gain of catalytic residue at Q133 (P = 0.1206);Gain of catalytic residue at Q133 (P = 0.1206);Gain of catalytic residue at Q133 (P = 0.1206);Gain of catalytic residue at Q133 (P = 0.1206);Gain of catalytic residue at Q133 (P = 0.1206);
MVP		0.98
ClinPred		0.95	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.11

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

Other links and lift over

dbSNP: rs397517959; hg19: chr2-105984137;