2-105396175-C-T

Variant names:

• chr2-105396175-C-T
• rs4851765
• NM_001318895.3:c.-25+472G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001318895.3(FHL2):​c.-25+472G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 152,132 control chromosomes in the GnomAD database, including 37,989 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.71 (37989 hom., cov: 32)
• Consequence: FHL2 NM_001318895.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.392
• Publications: 6 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]

FHL2 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 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.-25+472G>A		intron	N/A	NP_001305824.1	Q14192-1
	FHL2	NM_001039492.3		c.-25+472G>A		intron	N/A	NP_001034581.1	Q6I9R8
	FHL2	NM_001318894.1		c.-25+3047G>A		intron	N/A	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.-25+472G>A		intron	N/A	ENSP00000433567.2	Q14192-1
	FHL2	ENST00000322142.13	TSL:1	c.-25+472G>A		intron	N/A	ENSP00000322909.8	Q14192-1
	FHL2	ENST00000344213.9	TSL:1	c.-146+472G>A		intron	N/A	ENSP00000344266.5	Q14192-1

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107216 AN: 152014 Hom.: 37969 Cov.: 32

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.748

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.678

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.660

Gnomad OTH AF: 0.712

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.705 AC: 107288 AN: 152132 Hom.: 37989 Cov.: 32 AF XY: 0.710 AC XY: 52790 AN XY: 74372

African (AFR) AF: 0.758 AC: 31438 AN: 41498

American (AMR) AF: 0.748 AC: 11436 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2583 AN: 3468

East Asian (EAS) AF: 0.678 AC: 3505 AN: 5172

South Asian (SAS) AF: 0.634 AC: 3050 AN: 4814

European-Finnish (FIN) AF: 0.756 AC: 8000 AN: 10580

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.660 AC: 44905 AN: 67994

Other (OTH) AF: 0.710 AC: 1499 AN: 2112

Alfa AF: 0.672 Hom.: 42531

Bravo AF: 0.711

Asia WGS AF: 0.648 AC: 2256 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.98
DANN	Benign	0.53
PhyloP100		-0.39
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs4851765; hg19: chr2-106012632; COSMIC: COSV59079215;