rs1250346386

Variant names:

• chr14-34713091-G-A
• rs1250346386
• NM_138638.5:c.357C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_138638.5(CFL2):​c.357C>T​(p.Ser119Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,433,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CFL2 NM_138638.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.42
• 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 14-34713091-G-A is Benign according to our data. Variant chr14-34713091-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 465804.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.42 with no splicing effect.

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.357C>T	p.Ser119Ser	synonymous	Exon 3 of 4	NP_619579.1	Q549N0
	CFL2	NM_021914.8		c.357C>T	p.Ser119Ser	synonymous	Exon 3 of 4	NP_068733.1	Q9Y281-1
	CFL2	NM_001243645.2		c.306C>T	p.Ser102Ser	synonymous	Exon 3 of 4	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.357C>T	p.Ser119Ser	synonymous	Exon 3 of 4	ENSP00000298159.6	Q9Y281-1
	CFL2	ENST00000341223.8	TSL:1	c.357C>T	p.Ser119Ser	synonymous	Exon 3 of 4	ENSP00000340635.3	Q9Y281-1
	CFL2	ENST00000554470.5	TSL:1	n.*37C>T		non_coding_transcript_exon	Exon 3 of 4	ENSP00000450862.1	G3V2U0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1433848 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 711388

African (AFR) AF: 0.00 AC: 0 AN: 32508

American (AMR) AF: 0.00 AC: 0 AN: 40960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25708

East Asian (EAS) AF: 0.00 AC: 0 AN: 38180

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097216

Other (OTH) AF: 0.00 AC: 0 AN: 59224

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Benign	0.65
PhyloP100		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1250346386; hg19: chr14-35182297;