rs397515451

Variant names:

• chr14-34713546-C-T
• rs397515451
• NM_138638.5:c.19G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001243645.2(CFL2):​c.-33G>A variant causes a 5 prime UTR premature start codon gain 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFL2 NM_001243645.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.81
• Publications: 4 publications found

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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243645.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFL2	NM_138638.5	MANE Select	c.19G>A	p.Val7Met	missense	Exon 2 of 4	NP_619579.1	Q549N0
	CFL2	NM_001243645.2		c.-33G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001230574.1	Q9Y281-3
	CFL2	NM_021914.8		c.19G>A	p.Val7Met	missense	Exon 2 of 4	NP_068733.1	Q9Y281-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFL2	ENST00000298159.11	TSL:1 MANE Select	c.19G>A	p.Val7Met	missense	Exon 2 of 4	ENSP00000298159.6	Q9Y281-1
	CFL2	ENST00000341223.8	TSL:1	c.19G>A	p.Val7Met	missense	Exon 2 of 4	ENSP00000340635.3	Q9Y281-1
	CFL2	ENST00000554470.5	TSL:1	n.19G>A		non_coding_transcript_exon	Exon 2 of 4	ENSP00000450862.1	G3V2U0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Nemaline myopathy 7 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.80		Gain of disorder (P = 0.0311)
MVP		0.95
MPC		1.5
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.036	Neutral
Varity_R		0.51
gMVP		0.92
Mutation Taster		=198/102	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397515451; hg19: chr14-35182752;