Genetic Variant NM_001318895.3:c.174C>T (chr2-105373716-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001318895.3(FHL2):c.174C>T(p.Asp58Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,614,022 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: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

FHL2
NM_001318895.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.26

Publications

0 publications found

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]

FHL2 links:

ENSG00000238273 (HGNC:):

ENSG00000238273 links:

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]

C2orf49 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 2-105373716-G-A is Benign according to our data. Variant chr2-105373716-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 163492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.26 with no splicing effect.

BS2

High AC in GnomAd4 at 30 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FHL2	NM_001318895.3	MANE Select	c.174C>T	p.Asp58Asp	synonymous	Exon 4 of 7	NP_001305824.1
FHL2	NM_001039492.3		c.174C>T	p.Asp58Asp	synonymous	Exon 4 of 7	NP_001034581.1
FHL2	NM_001318894.1		c.174C>T	p.Asp58Asp	synonymous	Exon 3 of 6	NP_001305823.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FHL2	ENST00000530340.6	TSL:1 MANE Select	c.174C>T	p.Asp58Asp	synonymous	Exon 4 of 7	ENSP00000433567.2
FHL2	ENST00000322142.13	TSL:1	c.174C>T	p.Asp58Asp	synonymous	Exon 4 of 7	ENSP00000322909.8
FHL2	ENST00000344213.9	TSL:1	c.174C>T	p.Asp58Asp	synonymous	Exon 5 of 8	ENSP00000344266.5

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000151

AC:

AN:

251328

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000335

AC:

489

AN:

1461720

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

230

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.000411

AC:

457

AN:

1112000

Other (OTH)

AF:

0.000447

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000197

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000259

Hom.:

Bravo

AF:

0.000208

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asp58Asp in exon 3 of FHL2: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue, is not located within th e splice consensus sequence. It has been identified in 3/7020 European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs141208906). Asp58Asp in exon 3 of FHL2 (rs 141208906; allele frequency = 3/7020) **

Cardiomyopathy

Benign:1

Aug 16, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Primary dilated cardiomyopathy

Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.7

(source)

DANN

Benign

0.84

PhyloP100

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over