rs80358250

Positions:

• chr14-34713462-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.81

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain ADF-H (size 149) in uniprot entity COF2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_138638.5
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 8160.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-34713462-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFL2	NM_138638.5	c.103G>A	p.Ala35Thr	missense_variant	2/4	ENST00000298159.11	NP_619579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFL2	ENST00000298159.11	c.103G>A	p.Ala35Thr	missense_variant	2/4	1	NM_138638.5	ENSP00000298159	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Nemaline myopathy 7 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Mar 15, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;T;.;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.6	L;L;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.097	B;B;.;.
Vest4		0.78
MutPred		0.85		Gain of phosphorylation at A35 (P = 0.0478);Gain of phosphorylation at A35 (P = 0.0478);.;.;
MVP		0.89
MPC		0.98
ClinPred		0.95	D
GERP RS		6.2
Varity_R		0.45
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs80358250; hg19: chr14-35182668;