5-157294835-G-T

Variant names:

• chr5-157294835-G-T
• rs1554108163
• NM_001037333.3:c.260G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001037333.3(CYFIP2):​c.260G>T​(p.Arg87Leu) 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 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_001037333.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.90
• Publications: 1 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: Likely_pathogenic. The variant received 8 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, 0.936
• PP5: Variant 5-157294835-G-T is Pathogenic according to our data. Variant chr5-157294835-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 545427.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037333.3. 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.260G>T	p.Arg87Leu	missense	Exon 4 of 31	NP_001032410.1
	CYFIP2	NM_001291722.2		c.260G>T	p.Arg87Leu	missense	Exon 4 of 32	NP_001278651.1
	CYFIP2	NM_014376.4		c.260G>T	p.Arg87Leu	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.260G>T	p.Arg87Leu	missense	Exon 4 of 31	ENSP00000479968.1
	CYFIP2	ENST00000616178.4	TSL:1	c.260G>T	p.Arg87Leu	missense	Exon 4 of 32	ENSP00000479719.1
	CYFIP2	ENST00000618329.4	TSL:1	c.260G>T	p.Arg87Leu	missense	Exon 4 of 31	ENSP00000484819.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 65 Pathogenic:2

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely Pathogenic, for Epileptic encephalopathy, early infantile, 65, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (https://www.ncbi.nlm.nih.gov/pubmed/29534297). PS2 => De novo (paternity and maternity confirmed) (https://www.ncbi.nlm.nih.gov/pubmed/29534297).

Nov 17, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.81	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.69	P
Vest4		0.96
MutPred		0.82		Loss of catalytic residue at R87 (P = 0.0045)
MVP		0.93
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.82
gMVP		1.0
Mutation Taster		=211/89	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: rs1554108163; hg19: chr5-156721844;