rs201189319

Variant names:

• chr2-105386409-G-A
• rs201189319
• NM_001318895.3:c.108C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-105386409-G-A
• chr2-105386409-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001318899.2(FHL2):​c.-339C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000421 in 1,614,190 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: FHL2 NM_001318899.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0630
• Publications: 2 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]

FHL2 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-105386409-G-A is Benign according to our data. Variant chr2-105386409-G-A is described in ClinVar as Benign. ClinVar VariationId is 454289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 41 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318899.2. 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.108C>T	p.Phe36Phe	synonymous	Exon 3 of 7	NP_001305824.1	Q14192-1
	FHL2	NM_001318899.2		c.-339C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 8	NP_001305828.1
	FHL2	NM_001318897.2		c.-60C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001305826.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL2	ENST00000530340.6	TSL:1 MANE Select	c.108C>T	p.Phe36Phe	synonymous	Exon 3 of 7	ENSP00000433567.2	Q14192-1
	FHL2	ENST00000322142.13	TSL:1	c.108C>T	p.Phe36Phe	synonymous	Exon 3 of 7	ENSP00000322909.8	Q14192-1
	FHL2	ENST00000344213.9	TSL:1	c.108C>T	p.Phe36Phe	synonymous	Exon 4 of 8	ENSP00000344266.5	Q14192-1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000485 AC: 122 AN: 251378 AF XY: 0.000618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000437 AC: 639 AN: 1461874 Hom.: 5 Cov.: 31 AF XY: 0.000470 AC XY: 342 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00181 AC: 156 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.00573 AC: 33 AN: 5764

European-Non Finnish (NFE) AF: 0.000366 AC: 407 AN: 1111998

Other (OTH) AF: 0.000480 AC: 29 AN: 60396

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74466

African (AFR) AF: 0.0000481 AC: 2 AN: 41590

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000402 Hom.: 0

Bravo AF: 0.000249

EpiCase AF: 0.000600

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.67
DANN	Benign	0.68
PhyloP100		0.063
Mutation Taster		=99/1	polymorphism

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: rs201189319; hg19: chr2-106002866;