5-157294834-C-A

Variant names:

• chr5-157294834-C-A
• rs1131692231
• NM_001037333.3:c.259C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001291722.2(CYFIP2):​c.259C>A​(p.Arg87Ser) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R87P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYFIP2 NM_001291722.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.85
• Publications: 18 publications found

Genes affected

CYFIP2 (HGNC:13760): (cytoplasmic FMR1 interacting protein 2) Predicted to enable small GTPase binding activity. Involved in activation of cysteine-type endopeptidase activity; apoptotic process; and cell-cell adhesion. Located in perinuclear region of cytoplasm and synapse. Part of SCAR complex. Implicated in developmental and epileptic encephalopathy 65. [provided by Alliance of Genome Resources, Apr 2022]

CYFIP2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 65

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-157294835-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 545429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 5-157294834-C-A is Pathogenic according to our data. Variant chr5-157294834-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 802171.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291722.2. 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
	CYFIP2	NM_001037333.3	MANE Select	c.259C>A	p.Arg87Ser	missense	Exon 4 of 31	NP_001032410.1
	CYFIP2	NM_001291722.2		c.259C>A	p.Arg87Ser	missense	Exon 4 of 32	NP_001278651.1
	CYFIP2	NM_014376.4		c.259C>A	p.Arg87Ser	missense	Exon 4 of 31	NP_055191.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYFIP2	ENST00000620254.5	TSL:1 MANE Select	c.259C>A	p.Arg87Ser	missense	Exon 4 of 31	ENSP00000479968.1
	CYFIP2	ENST00000616178.4	TSL:1	c.259C>A	p.Arg87Ser	missense	Exon 4 of 32	ENSP00000479719.1
	CYFIP2	ENST00000618329.4	TSL:1	c.259C>A	p.Arg87Ser	missense	Exon 4 of 31	ENSP00000484819.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	CYFIP2-related disorder (1)
1	-	-	Developmental and epileptic encephalopathy, 65 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Benign	0.72	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.8
PrimateAI	Pathogenic	0.80	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.69	P
Vest4		0.93
MutPred		0.86		Loss of MoRF binding (P = 0.01)
MVP		0.95
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.83
gMVP		1.0
Mutation Taster		=191/109	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1131692231; hg19: chr5-156721843; COSMIC: COSV59037367;