NM_001318895.3:c.595C>A

Variant names:

• chr2-105363378-G-T
• rs373259092
• NM_001318895.3:c.595C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001318895.3(FHL2):​c.595C>A​(p.Arg199Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,752 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. R199H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FHL2 NM_001318895.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.52
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 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.595C>A	p.Arg199Ser	missense_variant	Exon 6 of 7	ENST00000530340.6	NP_001305824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL2	ENST00000530340.6	c.595C>A	p.Arg199Ser	missense_variant	Exon 6 of 7	1	NM_001318895.3	ENSP00000433567.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461752 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111962

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 08, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg199Ser variant in FHL2 has not been reported in the literature, but has b een identified in 1/4406 African American and 1/8600 European American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical sign ificance of the Arg199Ser variant. -

Cardiomyopathy Uncertain:1

Oct 21, 2015

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;.;D;D;D;D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	.;.;.;.;.;.;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;.;L;L;L;L;L
PhyloP100		4.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.5	.;D;D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.047	.;D;D;D;D;D;D
Sift4G	Uncertain	0.028	D;D;D;D;D;D;D
Polyphen		0.47	.;.;P;P;P;P;P
Vest4		0.56
MutPred		0.42		.;.;Gain of disorder (P = 0.0767);Gain of disorder (P = 0.0767);Gain of disorder (P = 0.0767);Gain of disorder (P = 0.0767);Gain of disorder (P = 0.0767);
MVP		0.98
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.72
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs373259092; hg19: chr2-105979835;