rs750884671

Variant names:

• chr2-105361363-A-C
• rs750884671
• NM_001318895.3:c.760T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-105361363-A-C
• chr2-105361363-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_001318895.3(FHL2):​c.760T>G​(p.Cys254Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FHL2 NM_001318895.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.27

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL2	NM_001318895.3	c.760T>G	p.Cys254Gly	missense_variant	Exon 7 of 7	ENST00000530340.6	NP_001305824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL2	ENST00000530340.6	c.760T>G	p.Cys254Gly	missense_variant	Exon 7 of 7	1	NM_001318895.3	ENSP00000433567.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250418 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135492

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 SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	.;.;D;D;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	.;.;.;.;.;.;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	.;.;H;H;H;H;H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-11	.;D;D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;D;D;D
Vest4		0.94
MutPred		0.76		.;.;Loss of methylation at K253 (P = 0.0298);Loss of methylation at K253 (P = 0.0298);Loss of methylation at K253 (P = 0.0298);Loss of methylation at K253 (P = 0.0298);Loss of methylation at K253 (P = 0.0298);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96

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

LitVar

Other links and lift over

dbSNP: rs750884671; hg19: chr2-105977820;