Genetic Variant CFL2:c.*2233delT (chr14-34710631-GA-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_138638.5(CFL2):c.*2233delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 436,424 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0035 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 1 hom. )

Consequence

CFL2
NM_138638.5 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.42

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00354 (538/152182) while in subpopulation AFR AF = 0.0125 (520/41510). AF 95% confidence interval is 0.0116. There are 5 homozygotes in GnomAd4. There are 254 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFL2	NM_138638.5 link	c.*2233delT		3_prime_UTR_variant	Exon 4 of 4	ENST00000298159.11	NP_619579.1	Q9Y281-1Q549N0

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CFL2	ENST00000298159 link	c.*2233delT	3_prime_UTR_variant	Exon 4 of 4	1	NM_138638.5	ENSP00000298159.6	Q9Y281-1
CFL2	ENST00000341223 link	c.*2233delT	3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000340635.3	Q9Y281-1
CFL2	ENST00000672517 link	c.*2233delT	3_prime_UTR_variant	Exon 5 of 5			ENSP00000500532.1	Q9Y281-1

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

538

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.000848

AC:

104

AN:

122696

AF XY:

0.000694

show subpopulations

Gnomad AFR exome

AF:

0.0137

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000391

Gnomad OTH exome

AF:

0.000265

GnomAD4 exome

AF:

0.000471

AC:

134

AN:

284242

Hom.:

Cov.:

AF XY:

0.000347

AC XY:

AN XY:

161606

show subpopulations

Gnomad4 AFR exome

AF:

0.0141

AC:

107

AN:

7582

Gnomad4 AMR exome

AF:

0.000689

AC:

AN:

23238

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

10140

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

9058

Gnomad4 SAS exome

AF:

0.0000365

AC:

AN:

54788

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

12550

Gnomad4 NFE exome

AF:

0.0000131

AC:

AN:

152506

Gnomad4 Remaining exome

AF:

0.000527

AC:

AN:

13294

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

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:

0.00354

AC:

538

AN:

152182

Hom.:

Cov.:

AF XY:

0.00341

AC XY:

254

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0125

AC:

0.0125271

AN:

0.0125271

Gnomad4 AMR

AF:

0.000720

AC:

0.000719707

AN:

0.000719707

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00331

AC:

0.00331439

AN:

0.00331439

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

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:

0.00191

Hom.:

Bravo

AF:

0.00450

Asia WGS

AF:

0.000582

AC:

AN:

3452

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nemaline Myopathy, Recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over