14-34713491-G-C

Variant names:

• chr14-34713491-G-C
• rs797045460
• NM_138638.5:c.74C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_138638.5(CFL2):​c.74C>G​(p.Thr25Arg) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFL2 NM_138638.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.03

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 Uncertain_significance. Variant got 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.34968454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFL2	NM_138638.5	c.74C>G	p.Thr25Arg	missense_variant	Exon 2 of 4	ENST00000298159.11	NP_619579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFL2	ENST00000298159.11	c.74C>G	p.Thr25Arg	missense_variant	Exon 2 of 4	1	NM_138638.5	ENSP00000298159.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 21, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	.;T;.;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.9	M;M;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.013	B;B;.;.
Vest4		0.50
MutPred		0.36		Gain of MoRF binding (P = 0.0275);Gain of MoRF binding (P = 0.0275);.;.;
MVP		0.87
MPC		1.5
ClinPred		0.92	D
GERP RS		6.2
Varity_R		0.68
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs797045460; hg19: chr14-35182697;