14-34711183-T-A

Variant names:

• chr14-34711183-T-A
• rs712301
• NM_138638.5:c.*1682A>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138638.5(CFL2):​c.*1682A>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 0.462 in 453,330 control chromosomes in the GnomAD database, including 51,733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16786 hom., cov: 32)
  • Exomes 𝑓: 0.47 (34947 hom.)
• Consequence: CFL2 NM_138638.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.165

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-34711183-T-A is Benign according to our data. Variant chr14-34711183-T-A is described in ClinVar as [Benign]. Clinvar id is 313082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFL2	NM_138638.5	c.*1682A>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.*1682A>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_138638.5	ENSP00000298159.6
CFL2	ENST00000341223	c.*1682A>T		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000340635.3
CFL2	ENST00000672517	c.*1682A>T		3_prime_UTR_variant	Exon 5 of 5			ENSP00000500532.1

Frequencies

GnomAD3 genomes AF: 0.455 AC: 68990 AN: 151744 Hom.: 16781 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.471

GnomAD3 exomes AF: 0.427 AC: 56979 AN: 133558 Hom.: 13462 AF XY: 0.433 AC XY: 31515 AN XY: 72820

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.540

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.377

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.478

GnomAD4 exome AF: 0.466 AC: 140615 AN: 301468 Hom.: 34947 Cov.: 0 AF XY: 0.461 AC XY: 79160 AN XY: 171764

Gnomad4 AFR exome AF: 0.330

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.542

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.375

Gnomad4 FIN exome AF: 0.593

Gnomad4 NFE exome AF: 0.539

Gnomad4 OTH exome AF: 0.473

GnomAD4 genome AF: 0.454 AC: 69019 AN: 151862 Hom.: 16786 Cov.: 32 AF XY: 0.454 AC XY: 33678 AN XY: 74230

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.531

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.606

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.465

Alfa AF: 0.502 Hom.: 3559

Bravo AF: 0.434

Asia WGS AF: 0.324 AC: 1129 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 7 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.52
DANN	Benign	0.54

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: rs712301; hg19: chr14-35180389;