14-34710827-C-A

Variant names:

• chr14-34710827-C-A
• rs9491
• NM_138638.5:c.*2038G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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 -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 VariationId 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.

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.*2038G>T		3_prime_UTR	Exon 4 of 4	NP_619579.1	Q549N0
	CFL2	NM_021914.8		c.*2038G>T		3_prime_UTR	Exon 4 of 4	NP_068733.1	Q9Y281-1
	CFL2	NM_001243645.2		c.*2038G>T		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.*2038G>T		3_prime_UTR	Exon 4 of 4	ENSP00000298159.6	Q9Y281-1
	CFL2	ENST00000341223.8	TSL:1	c.*2038G>T		3_prime_UTR	Exon 4 of 4	ENSP00000340635.3	Q9Y281-1
	CFL2	ENST00000672517.1		c.*2038G>T		3_prime_UTR	Exon 5 of 5	ENSP00000500532.1	Q9Y281-1

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

GnomAD2 exomes AF: 0.191 AC: 24956 AN: 130932 AF XY: 0.194

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 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

African (AFR) AF: 0.460 AC: 3907 AN: 8496

American (AMR) AF: 0.140 AC: 3815 AN: 27218

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 2197 AN: 10780

East Asian (EAS) AF: 0.181 AC: 1671 AN: 9210

South Asian (SAS) AF: 0.255 AC: 15194 AN: 59516

European-Finnish (FIN) AF: 0.127 AC: 1565 AN: 12362

Middle Eastern (MID) AF: 0.280 AC: 321 AN: 1148

European-Non Finnish (NFE) AF: 0.151 AC: 23932 AN: 158684

Other (OTH) AF: 0.194 AC: 2725 AN: 14028

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

African (AFR) AF: 0.457 AC: 18949 AN: 41456

American (AMR) AF: 0.179 AC: 2735 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3470

East Asian (EAS) AF: 0.192 AC: 992 AN: 5174

South Asian (SAS) AF: 0.265 AC: 1277 AN: 4822

European-Finnish (FIN) AF: 0.121 AC: 1276 AN: 10570

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10662 AN: 67986

Other (OTH) AF: 0.230 AC: 486 AN: 2116

Alfa AF: 0.188 Hom.: 2166

Bravo AF: 0.253

Asia WGS AF: 0.239 AC: 831 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Nemaline myopathy 7 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.55
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs9491; hg19: chr14-35180033;