NM_001037333.3:c.70G>A

Variant names:

• chr5-157285431-G-A
• NM_001037333.3:c.70G>A

Variant summary

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

The NM_001037333.3(CYFIP2):​c.70G>A​(p.Asp24Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,429,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYFIP2 NM_001037333.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.75
• Publications: 0 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):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 65

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYFIP2	NM_001037333.3	MANE Select	c.70G>A	p.Asp24Asn	missense	Exon 2 of 31	NP_001032410.1	Q96F07-2
	CYFIP2	NM_001291722.2		c.70G>A	p.Asp24Asn	missense	Exon 2 of 32	NP_001278651.1	Q96F07-1
	CYFIP2	NM_014376.4		c.70G>A	p.Asp24Asn	missense	Exon 2 of 31	NP_055191.2	Q96F07-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYFIP2	ENST00000620254.5	TSL:1 MANE Select	c.70G>A	p.Asp24Asn	missense	Exon 2 of 31	ENSP00000479968.1	Q96F07-2
	CYFIP2	ENST00000616178.4	TSL:1	c.70G>A	p.Asp24Asn	missense	Exon 2 of 32	ENSP00000479719.1	Q96F07-1
	CYFIP2	ENST00000618329.4	TSL:1	c.70G>A	p.Asp24Asn	missense	Exon 2 of 31	ENSP00000484819.1	Q96F07-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1429980 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 707948

African (AFR) AF: 0.00 AC: 0 AN: 32762

American (AMR) AF: 0.00 AC: 0 AN: 39892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25482

East Asian (EAS) AF: 0.00 AC: 0 AN: 38072

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1096538

Other (OTH) AF: 0.00 AC: 0 AN: 59330

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.55		Loss of disorder (P = 0.203)
MVP		0.62
MPC		1.6
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.37
gMVP		0.99
Mutation Taster		=8/92	disease causing

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

hg19: chr5-156712441;