rs2244182

Positions:

• chr2-105361446-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001318895.3(FHL2):​c.689-12C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,606,806 control chromosomes in the GnomAD database, including 27,056 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4349 hom., cov: 33)
  • Exomes 𝑓: 0.16 (22707 hom.)
• Consequence: FHL2 NM_001318895.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0005900
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.861

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 2-105361446-G-C is Benign according to our data. Variant chr2-105361446-G-C is described in ClinVar as [Benign]. Clinvar id is 48329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105361446-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL2	NM_001318895.3	c.689-12C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000530340.6	NP_001305824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL2	ENST00000530340.6	c.689-12C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001318895.3	ENSP00000433567	P1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32315 AN: 152008 Hom.: 4347 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.542

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.205

GnomAD3 exomes AF: 0.210 AC: 51251 AN: 244478 Hom.: 7401 AF XY: 0.199 AC XY: 26372 AN XY: 132202

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.284

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.564

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.157 AC: 228479 AN: 1454680 Hom.: 22707 Cov.: 31 AF XY: 0.156 AC XY: 113016 AN XY: 723240

Gnomad4 AFR exome AF: 0.336

Gnomad4 AMR exome AF: 0.273

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.526

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.213 AC: 32349 AN: 152126 Hom.: 4349 Cov.: 33 AF XY: 0.215 AC XY: 15996 AN XY: 74378

Gnomad4 AFR AF: 0.333

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.541

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.211

Alfa AF: 0.171 Hom.: 502

Bravo AF: 0.229

Asia WGS AF: 0.363 AC: 1263 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 16, 2012

689-12C>G in intron 5 of FHL2: This variant is not expected to have clinical sig nificance because it is not located within the splice consensus sequence and has been identified in 33% (1242/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS; dbSNP rs2244182). -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00059
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.010		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: rs2244182; hg19: chr2-105977903; COSMIC: COSV59078969; COSMIC: COSV59078969;