2-105386396-C-G

Position:

• chr2-105386396-C-G

Variant summary

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

The NM_001318895.3(FHL2):​c.121G>C​(p.Glu41Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E41K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FHL2 NM_001318895.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.11

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]

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/exons	MANE	UniProt
FHL2	NM_001318895.3	c.121G>C	p.Glu41Gln	missense_variant	3/7	ENST00000530340.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL2	ENST00000530340.6	c.121G>C	p.Glu41Gln	missense_variant	3/7	1	NM_001318895.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;.;D;D;D;.;D;D;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	.;.;.;.;.;T;.;D;T
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.6	.;.;L;L;L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	.;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.49
Sift	Benign	0.17	.;T;T;T;T;T;T;T;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T
Polyphen		0.85	.;.;P;P;P;.;P;P;.
Vest4		0.63
MutPred		0.35		.;.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.97
MPC		0.82
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.28

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: rs552625336; hg19: chr2-106002853;