14-34712907-CAA-AAC

Variant names:

• chr14-34712907-CAA-AAC
• NM_138638.5:c.457_459delTTGinsGTT
• CFL2 p.Leu153Val

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2 PP3

The NM_138638.5(CFL2):​c.457_459delTTGinsGTT​(p.Leu153Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFL2 NM_138638.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.24
• 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, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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 typical nemaline myopathy, nemaline myopathy 7.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFL2	NM_138638.5	MANE Select	c.457_459delTTGinsGTT	p.Leu153Val	missense	N/A	NP_619579.1	Q549N0
	CFL2	NM_021914.8		c.457_459delTTGinsGTT	p.Leu153Val	missense	N/A	NP_068733.1	Q9Y281-1
	CFL2	NM_001243645.2		c.406_408delTTGinsGTT	p.Leu136Val	missense	N/A	NP_001230574.1	Q9Y281-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFL2	ENST00000298159.11	TSL:1 MANE Select	c.457_459delTTGinsGTT	p.Leu153Val	missense	N/A	ENSP00000298159.6	Q9Y281-1
	CFL2	ENST00000341223.8	TSL:1	c.457_459delTTGinsGTT	p.Leu153Val	missense	N/A	ENSP00000340635.3	Q9Y281-1
	CFL2	ENST00000554470.5	TSL:1	n.*137_*139delTTGinsGTT		non_coding_transcript_exon	Exon 4 of 4	ENSP00000450862.1	G3V2U0

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-35182113;