14-34713491-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T25A) has been classified 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
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34968454).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFL2	NM_138638.5	MANE Select	c.74C>G	p.Thr25Arg	missense	Exon 2 of 4	NP_619579.1
	CFL2	NM_021914.8		c.74C>G	p.Thr25Arg	missense	Exon 2 of 4	NP_068733.1
	CFL2	NM_001243645.2		c.23C>G	p.Thr8Arg	missense	Exon 2 of 4	NP_001230574.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFL2	ENST00000298159.11	TSL:1 MANE Select	c.74C>G	p.Thr25Arg	missense	Exon 2 of 4	ENSP00000298159.6
	CFL2	ENST00000341223.8	TSL:1	c.74C>G	p.Thr25Arg	missense	Exon 2 of 4	ENSP00000340635.3
	CFL2	ENST00000554470.5	TSL:1	n.57+17C>G		intron	N/A	ENSP00000450862.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.9	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.39
Sift	Benign	0.16	T
Sift4G	Benign	0.11	T
Polyphen		0.013	B
Vest4		0.50
MutPred		0.36		Gain of MoRF binding (P = 0.0275)
MVP		0.87
MPC		1.5
ClinPred		0.92	D
GERP RS		6.2
PromoterAI		0.019	Neutral
Varity_R		0.68
gMVP		0.67
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs797045460; hg19: chr14-35182697;