rs1131692231

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-157294834-C-A
• chr5-157294834-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001037333.3(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. R87C) 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: 6.85

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-157294834-C-T is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the CYFIP2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 20 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: 6.0129 (above the threshold of 3.09). Trascript score misZ: 6.9267 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 65, developmental and epileptic encephalopathy, 76, undetermined early-onset epileptic encephalopathy.
• 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 id is 802171.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-157294834-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYFIP2	NM_001037333.3	c.259C>A	p.Arg87Ser	missense_variant	Exon 4 of 31	ENST00000620254.5	NP_001032410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYFIP2	ENST00000620254.5	c.259C>A	p.Arg87Ser	missense_variant	Exon 4 of 31	1	NM_001037333.3	ENSP00000479968.1

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:1

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CYFIP2-related disorder Pathogenic:1

Nov 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CYFIP2 c.259C>A variant is predicted to result in the amino acid substitution p.Arg87Ser. This variant and multiple other substitutions at this amino acid position (Cys, Leu, Pro, His) have been reported in 14 patients with neurodevelopmental disorder, being confirmed as de novo in 13 of the cases with both parents available for testing (Begemann. 2021. PubMed ID: 33149277). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;.;T;T;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Benign	0.72	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.;M
PrimateAI	Pathogenic	0.80	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.69	P;D;.;.;.;.;D
Vest4		0.93
MutPred		0.86		Loss of MoRF binding (P = 0.01);Loss of MoRF binding (P = 0.01);Loss of MoRF binding (P = 0.01);Loss of MoRF binding (P = 0.01);Loss of MoRF binding (P = 0.01);Loss of MoRF binding (P = 0.01);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131692231; hg19: chr5-156721843; COSMIC: COSV59037367;