rs2244182

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

2
Splicing: ADA: 0.0005900
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.861
Variant links:
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]

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ACMG classification

Classification made for transcript

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 UniProt
FHL2NM_001318895.3 linkuse as main transcriptc.689-12C>G splice_polypyrimidine_tract_variant, intron_variant ENST00000530340.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FHL2ENST00000530340.6 linkuse as main transcriptc.689-12C>G splice_polypyrimidine_tract_variant, intron_variant 1 NM_001318895.3 P1Q14192-1

Frequencies

GnomAD3 genomes
AF:
0.213
AC:
32315
AN:
152008
Hom.:
4347
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxJun 13, 2018This 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 submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 16, 2012689-12C>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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2244182; hg19: chr2-105977903; COSMIC: COSV59078969; COSMIC: COSV59078969; API