14-34710960-T-C

Variant names:

• chr14-34710960-T-C
• rs41528946
• NM_138638.5:c.*1905A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_138638.5(CFL2):​c.*1905A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 454,090 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (221 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (49 hom.)
• Consequence: CFL2 NM_138638.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 14-34710960-T-C is Benign according to our data. Variant chr14-34710960-T-C is described in ClinVar as [Benign]. Clinvar id is 313080.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFL2	NM_138638.5	c.*1905A>G		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.*1905A>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_138638.5	ENSP00000298159.6
CFL2	ENST00000341223	c.*1905A>G		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000340635.3
CFL2	ENST00000672517	c.*1905A>G		3_prime_UTR_variant	Exon 5 of 5			ENSP00000500532.1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4251 AN: 152182 Hom.: 218 Cov.: 33

Gnomad AFR AF: 0.0967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00643 AC: 839 AN: 130466 Hom.: 36 AF XY: 0.00542 AC XY: 386 AN XY: 71220

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00673

Gnomad ASJ exome AF: 0.00185

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000483

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00408 AC: 1230 AN: 301790 Hom.: 49 Cov.: 0 AF XY: 0.00319 AC XY: 549 AN XY: 171992

Gnomad4 AFR exome AF: 0.0982

Gnomad4 AMR exome AF: 0.00667

Gnomad4 ASJ exome AF: 0.00204

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000378

Gnomad4 OTH exome AF: 0.00748

GnomAD4 genome AF: 0.0280 AC: 4264 AN: 152300 Hom.: 221 Cov.: 33 AF XY: 0.0272 AC XY: 2022 AN XY: 74468

Gnomad4 AFR AF: 0.0967

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0129 Hom.: 23

Bravo AF: 0.0327

Asia WGS AF: 0.00577 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 7 Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.72

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: rs41528946; hg19: chr14-35180166;