chr2-105363295-G-T

Position:

• chr2-105363295-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001318895.3(FHL2):​c.678C>A​(p.Asn226Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N226N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: FHL2 NM_001318895.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.26

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:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14154363).
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL2	NM_001318895.3	c.678C>A	p.Asn226Lys	missense_variant	6/7	ENST00000530340.6	NP_001305824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL2	ENST00000530340.6	c.678C>A	p.Asn226Lys	missense_variant	6/7	1	NM_001318895.3	ENSP00000433567.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 26, 2013

The Asn226Lys variant in FHL2 has not been reported in individuals with cardiomy opathy or in large population studies. Asparagine (Asn) at position 226 is not c onserved across evolutionarily distant species and 3 other species (tetradon, pu fferfish and lamprey) have a lysine (Lys, this change) at this position, raising the possibility that change at this position may be tolerated. Computational an alyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, a nd SIFT) suggest that the Asn226Lys variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. Additional i nformation is needed to fully assess the clinical significance of the Asn226Lys variant. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 226 of the FHL2 protein (p.Asn226Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FHL2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179457). 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 with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Benign	0.42
DEOGEN2	Benign	0.26	.;.;T;T;T;T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	.;.;.;.;.;.;D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-2.0	.;.;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	3.5	.;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.89	.;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;B;B;B
Vest4		0.33
MutPred		0.47		.;.;Gain of methylation at N226 (P = 0.0075);Gain of methylation at N226 (P = 0.0075);Gain of methylation at N226 (P = 0.0075);Gain of methylation at N226 (P = 0.0075);Gain of methylation at N226 (P = 0.0075);
MVP		0.68
ClinPred		0.063	T
GERP RS		2.5
Varity_R		0.025

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: rs137869171; hg19: chr2-105979752;