FHL2 p.Gly44Arg

Variant names:

• chr2-105386387-C-G
• NM_001318895.3:c.130G>C
• FHL2 p.Gly44Arg

Your query was ambiguous. Multiple possible variants found:

• chr2-105386387-C-G
• chr2-105386387-C-T
• chr2-105386385-CCC-ACG
• chr2-105386385-CCC-GCG
• chr2-105386385-CCC-TCG
• chr2-105386385-CCC-TCT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001318895.3(FHL2):​c.130G>C​(p.Gly44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FHL2 NM_001318895.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80
• Publications: 0 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]

FHL2 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28195304).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318895.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL2	NM_001318895.3	MANE Select	c.130G>C	p.Gly44Arg	missense	Exon 3 of 7	NP_001305824.1	Q14192-1
	FHL2	NM_001039492.3		c.130G>C	p.Gly44Arg	missense	Exon 3 of 7	NP_001034581.1	Q6I9R8
	FHL2	NM_001318894.1		c.130G>C	p.Gly44Arg	missense	Exon 2 of 6	NP_001305823.1	Q2XQU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL2	ENST00000530340.6	TSL:1 MANE Select	c.130G>C	p.Gly44Arg	missense	Exon 3 of 7	ENSP00000433567.2	Q14192-1
	FHL2	ENST00000322142.13	TSL:1	c.130G>C	p.Gly44Arg	missense	Exon 3 of 7	ENSP00000322909.8	Q14192-1
	FHL2	ENST00000344213.9	TSL:1	c.130G>C	p.Gly44Arg	missense	Exon 4 of 8	ENSP00000344266.5	Q14192-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.18
Sift	Benign	0.56	T
Sift4G	Benign	0.54	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
Mutation Taster		=79/21	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-106002844;