14-34711960-T-C

Variant names:

• chr14-34711960-T-C
• rs117658440
• NM_138638.5:c.*905A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_138638.5(CFL2):​c.*905A>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 0.000557 in 454,362 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: CFL2 NM_138638.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.816
• Publications: 0 publications found

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]

CFL2 Gene-Disease associations (from GenCC):

• nemaline myopathy 7

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-34711960-T-C is Benign according to our data. Variant chr14-34711960-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 881373.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000414 (63/152328) while in subpopulation EAS AF = 0.00983 (51/5188). AF 95% confidence interval is 0.00768. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138638.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFL2	NM_138638.5	MANE Select	c.*905A>G		3_prime_UTR	Exon 4 of 4	NP_619579.1	Q549N0
	CFL2	NM_021914.8		c.*905A>G		3_prime_UTR	Exon 4 of 4	NP_068733.1	Q9Y281-1
	CFL2	NM_001243645.2		c.*905A>G		3_prime_UTR	Exon 4 of 4	NP_001230574.1	Q9Y281-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFL2	ENST00000298159.11	TSL:1 MANE Select	c.*905A>G		3_prime_UTR	Exon 4 of 4	ENSP00000298159.6	Q9Y281-1
	CFL2	ENST00000341223.8	TSL:1	c.*905A>G		3_prime_UTR	Exon 4 of 4	ENSP00000340635.3	Q9Y281-1
	CFL2	ENST00000672517.1		c.*905A>G		3_prime_UTR	Exon 5 of 5	ENSP00000500532.1	Q9Y281-1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00981

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000967 AC: 132 AN: 136512 AF XY: 0.00109

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00942

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000241

GnomAD4 exome AF: 0.000629 AC: 190 AN: 302034 Hom.: 1 Cov.: 0 AF XY: 0.000726 AC XY: 125 AN XY: 172130

African (AFR) AF: 0.00 AC: 0 AN: 8552

American (AMR) AF: 0.00 AC: 0 AN: 27268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10786

East Asian (EAS) AF: 0.00988 AC: 91 AN: 9210

South Asian (SAS) AF: 0.00156 AC: 93 AN: 59620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1150

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 158618

Other (OTH) AF: 0.000427 AC: 6 AN: 14040

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00983 AC: 51 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.000461

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Nemaline myopathy 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		0.82
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs117658440; hg19: chr14-35181166;