14-34711358-G-A

Position:

• chr14-34711358-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_138638.5(CFL2):​c.*1507C>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00118 in 454,454 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: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: CFL2 NM_138638.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.00

Genes affected

CFL2 (HGNC:1875): (cofilin 2) This gene encodes an intracellular protein that is involved in the regulation of actin-filament dynamics. This protein is a major component of intranuclear and cytoplasmic actin rods. It can bind G- and F-actin in a 1:1 ratio of cofilin to actin, and it reversibly controls actin polymerization and depolymerization in a pH-dependent manner. Mutations in this gene cause nemaline myopathy type 7, a form of congenital myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00118 (180/152230) while in subpopulation NFE AF= 0.00153 (104/68016). AF 95% confidence interval is 0.00129. There are 0 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFL2	NM_138638.5	c.*1507C>T		3_prime_UTR_variant	4/4	ENST00000298159.11	NP_619579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFL2	ENST00000298159.11	c.*1507C>T		3_prime_UTR_variant	4/4	1	NM_138638.5	ENSP00000298159	P1
CFL2	ENST00000341223.8	c.*1507C>T		3_prime_UTR_variant	4/4	1		ENSP00000340635	P1
CFL2	ENST00000672517.1	c.*1507C>T		3_prime_UTR_variant	5/5			ENSP00000500532	P1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00119 AC: 162 AN: 136650 Hom.: 0 AF XY: 0.00123 AC XY: 91 AN XY: 74194

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.000940

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000889

Gnomad FIN exome AF: 0.000928

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.00121

GnomAD4 exome AF: 0.00117 AC: 355 AN: 302224 Hom.: 0 Cov.: 0 AF XY: 0.000999 AC XY: 172 AN XY: 172254

Gnomad4 AFR exome AF: 0.000117

Gnomad4 AMR exome AF: 0.000953

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000671

Gnomad4 FIN exome AF: 0.000469

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.000926

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74426

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00118

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.94

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: rs139087926; hg19: chr14-35180564;