5-157309800-A-G

Variant names:

• chr5-157309800-A-G
• rs3207362
• NM_001037333.3:c.958A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001037333.3(CYFIP2):​c.958A>G​(p.Lys320Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CYFIP2 NM_001037333.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.34
• Publications: 16 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22537285).

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.958A>G	p.Lys320Glu	missense	Exon 10 of 31	NP_001032410.1
	CYFIP2	NM_001291722.2		c.958A>G	p.Lys320Glu	missense	Exon 10 of 32	NP_001278651.1
	CYFIP2	NM_014376.4		c.958A>G	p.Lys320Glu	missense	Exon 10 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.958A>G	p.Lys320Glu	missense	Exon 10 of 31	ENSP00000479968.1
	CYFIP2	ENST00000616178.4	TSL:1	c.958A>G	p.Lys320Glu	missense	Exon 10 of 32	ENSP00000479719.1
	CYFIP2	ENST00000618329.4	TSL:1	c.958A>G	p.Lys320Glu	missense	Exon 10 of 31	ENSP00000484819.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453784 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722098

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 43586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.00 AC: 0 AN: 84370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108452

Other (OTH) AF: 0.0000166 AC: 1 AN: 60122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.065
Sift	Benign	0.13	T
Sift4G	Benign	0.089	T
Polyphen		0.034	B
Vest4		0.25
MutPred		0.44		Loss of ubiquitination at K320 (P = 0.0326)
MVP		0.33
MPC		1.6
ClinPred		0.75	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.64
Mutation Taster		=78/22	polymorphism

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: rs3207362; hg19: chr5-156736808;