NM_001037333.3:c.9G>T

Variant names:

• chr5-157285370-G-T
• rs371578292
• NM_001037333.3:c.9G>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM2 BP4_Moderate BP6_Moderate BP7 BS2

The NM_001037333.3(CYFIP2):​c.9G>T​(p.Thr3Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000353 in 1,414,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T3T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CYFIP2 NM_001037333.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.243
• 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: Benign. The variant received -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-157285370-G-T is Benign according to our data. Variant chr5-157285370-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2832693.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.243 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.9G>T	p.Thr3Thr	synonymous	Exon 2 of 31	NP_001032410.1	Q96F07-2
	CYFIP2	NM_001291722.2		c.9G>T	p.Thr3Thr	synonymous	Exon 2 of 32	NP_001278651.1	Q96F07-1
	CYFIP2	NM_014376.4		c.9G>T	p.Thr3Thr	synonymous	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.9G>T	p.Thr3Thr	synonymous	Exon 2 of 31	ENSP00000479968.1	Q96F07-2
	CYFIP2	ENST00000616178.4	TSL:1	c.9G>T	p.Thr3Thr	synonymous	Exon 2 of 32	ENSP00000479719.1	Q96F07-1
	CYFIP2	ENST00000618329.4	TSL:1	c.9G>T	p.Thr3Thr	synonymous	Exon 2 of 31	ENSP00000484819.1	Q96F07-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1414882 Hom.: 0 Cov.: 31 AF XY: 0.00000572 AC XY: 4 AN XY: 699218

African (AFR) AF: 0.00 AC: 0 AN: 32314

American (AMR) AF: 0.00 AC: 0 AN: 37508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25322

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37114

South Asian (SAS) AF: 0.0000375 AC: 3 AN: 80010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1087830

Other (OTH) AF: 0.00 AC: 0 AN: 58754

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.1
DANN	Benign	0.65
PhyloP100		-0.24
Mutation Taster		=69/31	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: rs371578292; hg19: chr5-156712380;