rs115841332

Variant names:

• chr2-105361444-G-C
• rs115841332
• NM_001318895.3:c.689-10C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001450.4(FHL2):​c.689-10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000799 in 1,610,242 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (6 hom.)
• Consequence: FHL2 NM_001450.4 intron
• Scores: Splicing: ADA: 0.0005799
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.394
• Publications: 0 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]

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-105361444-G-C is Benign according to our data. Variant chr2-105361444-G-C is described in ClinVar as Benign. ClinVar VariationId is 48328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000449 (655/1457918) while in subpopulation AFR AF = 0.0166 (554/33324). AF 95% confidence interval is 0.0155. There are 6 homozygotes in GnomAdExome4. There are 269 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 632 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001450.4. 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.689-10C>G		intron	N/A	NP_001305824.1
	FHL2	NM_001039492.3		c.689-10C>G		intron	N/A	NP_001034581.1
	FHL2	NM_001318894.1		c.689-10C>G		intron	N/A	NP_001305823.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL2	ENST00000530340.6	TSL:1 MANE Select	c.689-10C>G		intron	N/A	ENSP00000433567.2
	FHL2	ENST00000322142.13	TSL:1	c.689-10C>G		intron	N/A	ENSP00000322909.8
	FHL2	ENST00000344213.9	TSL:1	c.689-10C>G		intron	N/A	ENSP00000344266.5

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 632 AN: 152206 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

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: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00112 AC: 275 AN: 245218 AF XY: 0.000837

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000534

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000449 AC: 655 AN: 1457918 Hom.: 6 Cov.: 31 AF XY: 0.000371 AC XY: 269 AN XY: 724932

African (AFR) AF: 0.0166 AC: 554 AN: 33324

American (AMR) AF: 0.000612 AC: 27 AN: 44128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5742

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1109964

Other (OTH) AF: 0.000879 AC: 53 AN: 60264

GnomAD4 genome AF: 0.00415 AC: 632 AN: 152324 Hom.: 6 Cov.: 32 AF XY: 0.00381 AC XY: 284 AN XY: 74492

African (AFR) AF: 0.0141 AC: 588 AN: 41578

American (AMR) AF: 0.00255 AC: 39 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00482

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiomyopathy (1)
-	-	1	not specified (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.59
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00058
dbscSNV1_RF	Benign	0.054
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

Other links and lift over

dbSNP: rs115841332; hg19: chr2-105977901;