rs11124029

Variant names:

• chr2-105361304-G-A
• rs11124029
• NM_001318895.3:c.819C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001318895.3(FHL2):​c.819C>T​(p.Pro273Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,613,040 control chromosomes in the GnomAD database, including 27,859 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2145 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25714 hom.)
• Consequence: FHL2 NM_001318895.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.19
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-105361304-G-A is Benign according to our data. Variant chr2-105361304-G-A is described in ClinVar as Benign. ClinVar VariationId is 48332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.19 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL2	NM_001318895.3	MANE Select	c.819C>T	p.Pro273Pro	synonymous	Exon 7 of 7	NP_001305824.1
	FHL2	NM_001039492.3		c.819C>T	p.Pro273Pro	synonymous	Exon 7 of 7	NP_001034581.1
	FHL2	NM_001318894.1		c.819C>T	p.Pro273Pro	synonymous	Exon 6 of 6	NP_001305823.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL2	ENST00000530340.6	TSL:1 MANE Select	c.819C>T	p.Pro273Pro	synonymous	Exon 7 of 7	ENSP00000433567.2
	FHL2	ENST00000322142.13	TSL:1	c.819C>T	p.Pro273Pro	synonymous	Exon 7 of 7	ENSP00000322909.8
	FHL2	ENST00000344213.9	TSL:1	c.819C>T	p.Pro273Pro	synonymous	Exon 8 of 8	ENSP00000344266.5

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24171 AN: 152098 Hom.: 2147 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.158 AC: 39675 AN: 250382 AF XY: 0.162

Gnomad AFR exome AF: 0.0995

Gnomad AMR exome AF: 0.0914

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.0253

Gnomad FIN exome AF: 0.247

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.182 AC: 266232 AN: 1460824 Hom.: 25714 Cov.: 31 AF XY: 0.182 AC XY: 132086 AN XY: 726712

African (AFR) AF: 0.0978 AC: 3271 AN: 33438

American (AMR) AF: 0.0962 AC: 4293 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5659 AN: 26116

East Asian (EAS) AF: 0.0213 AC: 847 AN: 39678

South Asian (SAS) AF: 0.129 AC: 11126 AN: 86086

European-Finnish (FIN) AF: 0.243 AC: 13002 AN: 53416

Middle Eastern (MID) AF: 0.196 AC: 1132 AN: 5764

European-Non Finnish (NFE) AF: 0.195 AC: 216296 AN: 1111378

Other (OTH) AF: 0.176 AC: 10606 AN: 60340

GnomAD4 genome AF: 0.159 AC: 24170 AN: 152216 Hom.: 2145 Cov.: 32 AF XY: 0.160 AC XY: 11901 AN XY: 74424

African (AFR) AF: 0.102 AC: 4220 AN: 41542

American (AMR) AF: 0.139 AC: 2121 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 748 AN: 3470

East Asian (EAS) AF: 0.0253 AC: 131 AN: 5188

South Asian (SAS) AF: 0.120 AC: 578 AN: 4824

European-Finnish (FIN) AF: 0.251 AC: 2655 AN: 10580

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13078 AN: 67994

Other (OTH) AF: 0.165 AC: 349 AN: 2114

Alfa AF: 0.180 Hom.: 1722

Bravo AF: 0.149

Asia WGS AF: 0.0810 AC: 282 AN: 3478

EpiCase AF: 0.202

EpiControl AF: 0.200

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.41
DANN	Benign	0.61
PhyloP100		-4.2
Mutation Taster		=94/6	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: rs11124029; hg19: chr2-105977761; COSMIC: COSV59080694; COSMIC: COSV59080694;