14-34710827-C-A

Position:

• chr14-34710827-C-A

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.*2038G>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 0.204 in 453,508 control chromosomes in the GnomAD database, including 11,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5968 hom., cov: 32)
  • Exomes 𝑓: 0.18 (5917 hom.)
• Consequence: CFL2 NM_138638.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.208

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=-0.84).
• BP6: Variant 14-34710827-C-A is Benign according to our data. Variant chr14-34710827-C-A is described in ClinVar as [Benign]. Clinvar id is 313079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFL2	NM_138638.5	c.*2038G>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.*2038G>T		3_prime_UTR_variant	4/4	1	NM_138638.5	ENSP00000298159	P1
CFL2	ENST00000341223.8	c.*2038G>T		3_prime_UTR_variant	4/4	1		ENSP00000340635	P1
CFL2	ENST00000672517.1	c.*2038G>T		3_prime_UTR_variant	5/5			ENSP00000500532	P1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37336 AN: 151946 Hom.: 5963 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.231

GnomAD3 exomes AF: 0.191 AC: 24956 AN: 130932 Hom.: 2861 AF XY: 0.194 AC XY: 13885 AN XY: 71492

Gnomad AFR exome AF: 0.470

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.255

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.184 AC: 55327 AN: 301442 Hom.: 5917 Cov.: 0 AF XY: 0.191 AC XY: 32736 AN XY: 171792

Gnomad4 AFR exome AF: 0.460

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.181

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.194

GnomAD4 genome AF: 0.246 AC: 37380 AN: 152066 Hom.: 5968 Cov.: 32 AF XY: 0.243 AC XY: 18091 AN XY: 74334

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.230

Alfa AF: 0.184 Hom.: 1666

Bravo AF: 0.253

Asia WGS AF: 0.239 AC: 831 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 7 Benign:1

Benign, 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 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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.55

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: rs9491; hg19: chr14-35180033;