rs3087523

Variant names:

• chr2-105361319-G-A
• rs3087523
• NM_001318895.3:c.804C>T
• FHL2 p.Asp268Asp

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001318895.3(FHL2):​c.804C>T​(p.Asp268Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,613,654 control chromosomes in the GnomAD database, including 10,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (710 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9657 hom.)
• Consequence: FHL2 NM_001318895.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.653
• Publications: 21 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-105361319-G-A is Benign according to our data. Variant chr2-105361319-G-A is described in ClinVar as Benign. ClinVar VariationId is 48331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.653 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

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.804C>T	p.Asp268Asp	synonymous	Exon 7 of 7	NP_001305824.1	Q14192-1
	FHL2	NM_001039492.3		c.804C>T	p.Asp268Asp	synonymous	Exon 7 of 7	NP_001034581.1	Q6I9R8
	FHL2	NM_001318894.1		c.804C>T	p.Asp268Asp	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.804C>T	p.Asp268Asp	synonymous	Exon 7 of 7	ENSP00000433567.2	Q14192-1
	FHL2	ENST00000322142.13	TSL:1	c.804C>T	p.Asp268Asp	synonymous	Exon 7 of 7	ENSP00000322909.8	Q14192-1
	FHL2	ENST00000344213.9	TSL:1	c.804C>T	p.Asp268Asp	synonymous	Exon 8 of 8	ENSP00000344266.5	Q14192-1

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 13176 AN: 152116 Hom.: 710 Cov.: 32

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0927

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.0939

GnomAD2 exomes AF: 0.0936 AC: 23481 AN: 250918 AF XY: 0.0934

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.0998

Gnomad ASJ exome AF: 0.0901

Gnomad EAS exome AF: 0.0253

Gnomad FIN exome AF: 0.0975

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.111 AC: 161934 AN: 1461420 Hom.: 9657 Cov.: 32 AF XY: 0.109 AC XY: 79500 AN XY: 727036

African (AFR) AF: 0.0230 AC: 770 AN: 33474

American (AMR) AF: 0.100 AC: 4480 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 2341 AN: 26128

East Asian (EAS) AF: 0.0207 AC: 822 AN: 39688

South Asian (SAS) AF: 0.0548 AC: 4727 AN: 86220

European-Finnish (FIN) AF: 0.101 AC: 5405 AN: 53418

Middle Eastern (MID) AF: 0.0882 AC: 509 AN: 5768

European-Non Finnish (NFE) AF: 0.123 AC: 136704 AN: 1111634

Other (OTH) AF: 0.102 AC: 6176 AN: 60378

GnomAD4 genome AF: 0.0866 AC: 13179 AN: 152234 Hom.: 710 Cov.: 32 AF XY: 0.0849 AC XY: 6318 AN XY: 74432

African (AFR) AF: 0.0257 AC: 1067 AN: 41542

American (AMR) AF: 0.108 AC: 1646 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0927 AC: 322 AN: 3472

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5182

South Asian (SAS) AF: 0.0516 AC: 248 AN: 4806

European-Finnish (FIN) AF: 0.0995 AC: 1055 AN: 10604

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8492 AN: 68016

Other (OTH) AF: 0.0929 AC: 196 AN: 2110

Alfa AF: 0.109 Hom.: 1562

Bravo AF: 0.0849

Asia WGS AF: 0.0320 AC: 110 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.21
DANN	Benign	0.42
PhyloP100		-0.65
Mutation Taster		=99/1	polymorphism (auto)

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

dbSNP: rs3087523;

hg19: chr2-105977776;

COSMIC: COSV59079045;

COSMIC: COSV59079045;