Genetic Variant CFL2:c.*1036G>A (chr14-34711829-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_138638.5(CFL2):c.*1036G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 453,706 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0040 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0052 ( 7 hom. )

Consequence

CFL2
NM_138638.5 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.205

Publications

1 publications found

Variant links:

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

CFL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 14-34711829-C-T is Benign according to our data. Variant chr14-34711829-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 313086.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00402 (611/152134) while in subpopulation SAS AF = 0.00767 (37/4822). AF 95% confidence interval is 0.00572. There are 2 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CFL2	NM_138638.5	MANE Select	c.*1036G>A	3_prime_UTR	Exon 4 of 4	NP_619579.1	Q549N0
CFL2	NM_021914.8		c.*1036G>A	3_prime_UTR	Exon 4 of 4	NP_068733.1	Q9Y281-1
CFL2	NM_001243645.2		c.*1036G>A	3_prime_UTR	Exon 4 of 4	NP_001230574.1	Q9Y281-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CFL2	ENST00000298159.11	TSL:1 MANE Select	c.*1036G>A	3_prime_UTR	Exon 4 of 4	ENSP00000298159.6	Q9Y281-1
CFL2	ENST00000341223.8	TSL:1	c.*1036G>A	3_prime_UTR	Exon 4 of 4	ENSP00000340635.3	Q9Y281-1
CFL2	ENST00000672517.1		c.*1036G>A	3_prime_UTR	Exon 5 of 5	ENSP00000500532.1	Q9Y281-1

Frequencies

GnomAD3 genomes

AF:

0.00402

AC:

611

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00472

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00767

Gnomad FIN

AF:

0.00218

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00618

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00422

AC:

573

AN:

135740

AF XY:

0.00455

show subpopulations

Gnomad AFR exome

AF:

0.000622

Gnomad AMR exome

AF:

0.00453

Gnomad ASJ exome

AF:

0.000603

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00168

Gnomad NFE exome

AF:

0.00546

Gnomad OTH exome

AF:

0.00679

GnomAD4 exome

AF:

0.00516

AC:

1556

AN:

301572

Hom.:

Cov.:

AF XY:

0.00557

AC XY:

958

AN XY:

171844

show subpopulations

African (AFR)

AF:

0.000586

AC:

AN:

8528

American (AMR)

AF:

0.00453

AC:

123

AN:

27172

Ashkenazi Jewish (ASJ)

AF:

0.000464

AC:

AN:

10776

East Asian (EAS)

AF:

0.00

AC:

AN:

9210

South Asian (SAS)

AF:

0.00576

AC:

342

AN:

59324

European-Finnish (FIN)

AF:

0.00164

AC:

AN:

12774

Middle Eastern (MID)

AF:

0.0253

AC:

AN:

1146

European-Non Finnish (NFE)

AF:

0.00586

AC:

929

AN:

158618

Other (OTH)

AF:

0.00727

AC:

102

AN:

14024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

191

287

382

478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00402

AC:

611

AN:

152134

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

299

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000940

AC:

AN:

41508

American (AMR)

AF:

0.00472

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00767

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00218

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00618

AC:

420

AN:

68006

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

127

159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00440

Hom.:

Bravo

AF:

0.00391

Asia WGS

AF:

0.00231

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nemaline myopathy 7 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.60

PhyloP100

-0.20

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over