Genetic Variant CFL2:p.Ala35Thr (chr14-34713462-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_138638.5(CFL2):c.103G>A(p.Ala35Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

CFL2
NM_138638.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 7.81

Publications

11 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CFL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.6121 (below the threshold of 3.09). Trascript score misZ: 1.3379 (below the threshold of 3.09). GenCC associations: The gene is linked to nemaline myopathy 7, typical nemaline myopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

PP5

Variant 14-34713462-C-T is Pathogenic according to our data. Variant chr14-34713462-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8160.Status of the report is no_assertion_criteria_provided, 0 stars.

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	HGVSp	Effect	Exon Rank	Protein
CFL2	NM_138638.5	MANE Select	c.103G>A	p.Ala35Thr	missense	Exon 2 of 4	NP_619579.1
CFL2	NM_021914.8		c.103G>A	p.Ala35Thr	missense	Exon 2 of 4	NP_068733.1
CFL2	NM_001243645.2		c.52G>A	p.Ala18Thr	missense	Exon 2 of 4	NP_001230574.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CFL2	ENST00000298159.11	TSL:1 MANE Select	c.103G>A	p.Ala35Thr	missense	Exon 2 of 4	ENSP00000298159.6
CFL2	ENST00000341223.8	TSL:1	c.103G>A	p.Ala35Thr	missense	Exon 2 of 4	ENSP00000340635.3
CFL2	ENST00000554470.5	TSL:1	n.57+46G>A		intron	N/A	ENSP00000450862.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Nemaline myopathy 7

Pathogenic:2

Jan 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Mar 15, 2012

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.6

PhyloP100

7.8

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.45

Sift

Benign

0.18

Sift4G

Benign

0.44

Polyphen

0.097

Vest4

0.78

MutPred

0.85

Gain of phosphorylation at A35 (P = 0.0478)

MVP

0.89

MPC

0.98

ClinPred

0.95

GERP RS

6.2

PromoterAI

0.016

Neutral

(source)

Varity_R

0.45

gMVP

0.71

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over