chr2-105363273-C-A

Variant names:

• chr2-105363273-C-A
• rs2278502
• NM_001318895.3:c.688+12G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001450.4(FHL2):​c.688+12G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,611,904 control chromosomes in the GnomAD database, including 111,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7902 hom., cov: 32)
  • Exomes 𝑓: 0.37 (103863 hom.)
• Consequence: FHL2 NM_001450.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.336
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-105363273-C-A is Benign according to our data. Variant chr2-105363273-C-A is described in ClinVar as Benign. ClinVar VariationId is 48327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

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.688+12G>T		intron	N/A	NP_001305824.1
	FHL2	NM_001039492.3		c.688+12G>T		intron	N/A	NP_001034581.1
	FHL2	NM_001318894.1		c.688+12G>T		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.688+12G>T		intron	N/A	ENSP00000433567.2
	FHL2	ENST00000322142.13	TSL:1	c.688+12G>T		intron	N/A	ENSP00000322909.8
	FHL2	ENST00000344213.9	TSL:1	c.688+12G>T		intron	N/A	ENSP00000344266.5

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47312 AN: 151946 Hom.: 7902 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.309

GnomAD2 exomes AF: 0.332 AC: 82844 AN: 249662 AF XY: 0.341

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.323

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.377

Gnomad NFE exome AF: 0.380

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.372 AC: 543657 AN: 1459840 Hom.: 103863 Cov.: 34 AF XY: 0.373 AC XY: 271137 AN XY: 726022

African (AFR) AF: 0.172 AC: 5754 AN: 33468

American (AMR) AF: 0.269 AC: 12022 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 8397 AN: 26076

East Asian (EAS) AF: 0.188 AC: 7451 AN: 39646

South Asian (SAS) AF: 0.374 AC: 32208 AN: 86102

European-Finnish (FIN) AF: 0.379 AC: 20211 AN: 53374

Middle Eastern (MID) AF: 0.302 AC: 1740 AN: 5762

European-Non Finnish (NFE) AF: 0.391 AC: 434315 AN: 1110466

Other (OTH) AF: 0.357 AC: 21559 AN: 60314

GnomAD4 genome AF: 0.311 AC: 47327 AN: 152064 Hom.: 7902 Cov.: 32 AF XY: 0.309 AC XY: 22989 AN XY: 74326

African (AFR) AF: 0.185 AC: 7671 AN: 41482

American (AMR) AF: 0.311 AC: 4757 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1102 AN: 3470

East Asian (EAS) AF: 0.198 AC: 1026 AN: 5178

South Asian (SAS) AF: 0.365 AC: 1754 AN: 4810

European-Finnish (FIN) AF: 0.371 AC: 3921 AN: 10572

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26017 AN: 67952

Other (OTH) AF: 0.308 AC: 651 AN: 2114

Alfa AF: 0.323 Hom.: 3525

Bravo AF: 0.298

Asia WGS AF: 0.298 AC: 1036 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.082
DANN	Benign	0.62
PhyloP100		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2278502; hg19: chr2-105979730; COSMIC: COSV59079940; COSMIC: COSV59079940;