14-34711829-C-T

Variant names:

• chr14-34711829-C-T
• rs150492527
• NM_138638.5:c.*1036G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_138638.5(CFL2):​c.*1036G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 453,706 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (7 hom.)
• Consequence: CFL2 NM_138638.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.205

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 14-34711829-C-T is Benign according to our data. Variant chr14-34711829-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 313086.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00402 (611/152134) while in subpopulation SAS AF= 0.00767 (37/4822). AF 95% confidence interval is 0.00572. There are 2 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFL2	NM_138638.5	c.*1036G>A		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.*1036G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_138638.5	ENSP00000298159.6

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 611 AN: 152016 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.00218

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00618

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00422 AC: 573 AN: 135740 Hom.: 3 AF XY: 0.00455 AC XY: 335 AN XY: 73672

Gnomad AFR exome AF: 0.000622

Gnomad AMR exome AF: 0.00453

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00537

Gnomad FIN exome AF: 0.00168

Gnomad NFE exome AF: 0.00546

Gnomad OTH exome AF: 0.00679

GnomAD4 exome AF: 0.00516 AC: 1556 AN: 301572 Hom.: 7 Cov.: 0 AF XY: 0.00557 AC XY: 958 AN XY: 171844

Gnomad4 AFR exome AF: 0.000586

Gnomad4 AMR exome AF: 0.00453

Gnomad4 ASJ exome AF: 0.000464

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00576

Gnomad4 FIN exome AF: 0.00164

Gnomad4 NFE exome AF: 0.00586

Gnomad4 OTH exome AF: 0.00727

GnomAD4 genome AF: 0.00402 AC: 611 AN: 152134 Hom.: 2 Cov.: 33 AF XY: 0.00402 AC XY: 299 AN XY: 74354

Gnomad4 AFR AF: 0.000940

Gnomad4 AMR AF: 0.00472

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.00218

Gnomad4 NFE AF: 0.00618

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00440 Hom.: 0

Bravo AF: 0.00391

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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. -

not provided Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFL2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.60

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: rs150492527; hg19: chr14-35181035;