rs137869171

Variant names:

• chr2-105363295-G-A
• rs137869171
• NM_001318895.3:c.678C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-105363295-G-A
• chr2-105363295-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001318895.3(FHL2):​c.678C>T​(p.Asn226Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,124 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (6 hom., cov: 32)
  • Exomes 𝑓: 0.010 (98 hom.)
• Consequence: FHL2 NM_001318895.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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:):

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

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-105363295-G-A is Benign according to our data. Variant chr2-105363295-G-A is described in ClinVar as [Benign]. Clinvar id is 48326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105363295-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.26 with no splicing effect.
• BS2: High AC in GnomAd4 at 1168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL2	NM_001318895.3	c.678C>T	p.Asn226Asn	synonymous_variant	Exon 6 of 7	ENST00000530340.6	NP_001305824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL2	ENST00000530340.6	c.678C>T	p.Asn226Asn	synonymous_variant	Exon 6 of 7	1	NM_001318895.3	ENSP00000433567.2

Frequencies

GnomAD3 genomes AF: 0.00768 AC: 1168 AN: 152174 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00895

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00686 AC: 1723 AN: 251110 Hom.: 17 AF XY: 0.00640 AC XY: 869 AN XY: 135700

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00897

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00930

Gnomad NFE exome AF: 0.00983

Gnomad OTH exome AF: 0.00915

GnomAD4 exome AF: 0.0104 AC: 15177 AN: 1461832 Hom.: 98 Cov.: 32 AF XY: 0.0101 AC XY: 7334 AN XY: 727214

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00906

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00889

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.00873

GnomAD4 genome AF: 0.00767 AC: 1168 AN: 152292 Hom.: 6 Cov.: 32 AF XY: 0.00803 AC XY: 598 AN XY: 74490

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00895

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00888 Hom.: 5

Bravo AF: 0.00757

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asn226Asn in Exon 05 of FHL2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 1.3% (92/7020) of Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs137869171). -

Cardiomyopathy Benign:1

Sep 14, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary dilated cardiomyopathy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FHL2-related disorder Benign:1

May 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.7
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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;