14-34710581-G-A

Variant names:

• chr14-34710581-G-A
• rs372609152
• NM_138638.5:c.*2284C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_138638.5(CFL2):​c.*2284C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 432,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: CFL2 NM_138638.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.201

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000217 (33/152240) while in subpopulation EAS AF= 0.00502 (26/5182). AF 95% confidence interval is 0.00352. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 rank	MANE	Protein	UniProt
CFL2	NM_138638.5	c.*2284C>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000298159.11	NP_619579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFL2	ENST00000298159	c.*2284C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_138638.5	ENSP00000298159.6
CFL2	ENST00000341223	c.*2284C>T		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000340635.3
CFL2	ENST00000672517	c.*2284C>T		3_prime_UTR_variant	Exon 5 of 5			ENSP00000500532.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000396 AC: 48 AN: 121168 Hom.: 0 AF XY: 0.000319 AC XY: 21 AN XY: 65746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00417

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000541

GnomAD4 exome AF: 0.000225 AC: 63 AN: 280122 Hom.: 1 Cov.: 0 AF XY: 0.000233 AC XY: 37 AN XY: 158966

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000878

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00335

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000200

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74438

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000208

Asia WGS AF: 0.00670 AC: 23 AN: 3448

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 7 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.65

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: rs372609152; hg19: chr14-35179787;