rs750539692

Variant names:

• chr2-105363464-G-A
• rs750539692
• NM_001318895.3:c.509C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001318895.3(FHL2):​c.509C>T​(p.Thr170Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,276 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FHL2 NM_001318895.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91
• Publications: 1 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]

ENSG00000238273 (HGNC:):

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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27955714).

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.509C>T	p.Thr170Ile	missense	Exon 6 of 7	NP_001305824.1	Q14192-1
	FHL2	NM_001039492.3		c.509C>T	p.Thr170Ile	missense	Exon 6 of 7	NP_001034581.1	Q6I9R8
	FHL2	NM_001318894.1		c.509C>T	p.Thr170Ile	missense	Exon 5 of 6	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.509C>T	p.Thr170Ile	missense	Exon 6 of 7	ENSP00000433567.2	Q14192-1
	FHL2	ENST00000322142.13	TSL:1	c.509C>T	p.Thr170Ile	missense	Exon 6 of 7	ENSP00000322909.8	Q14192-1
	FHL2	ENST00000344213.9	TSL:1	c.509C>T	p.Thr170Ile	missense	Exon 7 of 8	ENSP00000344266.5	Q14192-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000850 AC: 2 AN: 235272 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455276 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723186

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 43616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25858

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39514

South Asian (SAS) AF: 0.00 AC: 0 AN: 84918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108974

Other (OTH) AF: 0.00 AC: 0 AN: 60184

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.54	D
PhyloP100		6.9
Vest4		0.32
MVP		0.51
ClinPred		0.95	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
Mutation Taster		=30/70	disease causing

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: rs750539692; hg19: chr2-105979921;