2-105361322-C-T

Variant names:

• chr2-105361322-C-T
• rs1573266848
• NM_001318895.3:c.801G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001318895.3(FHL2):​c.801G>A​(p.Arg267Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FHL2 NM_001318895.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0500
• 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]

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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 2-105361322-C-T is Benign according to our data. Variant chr2-105361322-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 758309.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.05 with no splicing effect.

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.801G>A	p.Arg267Arg	synonymous	Exon 7 of 7	NP_001305824.1	Q14192-1
	FHL2	NM_001039492.3		c.801G>A	p.Arg267Arg	synonymous	Exon 7 of 7	NP_001034581.1	Q6I9R8
	FHL2	NM_001318894.1		c.801G>A	p.Arg267Arg	synonymous	Exon 6 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.801G>A	p.Arg267Arg	synonymous	Exon 7 of 7	ENSP00000433567.2	Q14192-1
	FHL2	ENST00000322142.13	TSL:1	c.801G>A	p.Arg267Arg	synonymous	Exon 7 of 7	ENSP00000322909.8	Q14192-1
	FHL2	ENST00000344213.9	TSL:1	c.801G>A	p.Arg267Arg	synonymous	Exon 8 of 8	ENSP00000344266.5	Q14192-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461706 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727158

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: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.7
DANN	Benign	0.61
PhyloP100		0.050
Mutation Taster		=91/9	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

Other links and lift over

dbSNP: rs1573266848; hg19: chr2-105977779; COSMIC: COSV59079759; COSMIC: COSV59079759;