5-157285452-C-T

Variant names:

• chr5-157285452-C-T
• rs1461152506
• NM_001037333.3:c.91C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001037333.3(CYFIP2):​c.91C>T​(p.Pro31Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,540 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: 7.0e-7 (0 hom.)
• Consequence: CYFIP2 NM_001037333.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

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 Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYFIP2	NM_001037333.3	c.91C>T	p.Pro31Ser	missense_variant	Exon 2 of 31	ENST00000620254.5	NP_001032410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYFIP2	ENST00000620254.5	c.91C>T	p.Pro31Ser	missense_variant	Exon 2 of 31	1	NM_001037333.3	ENSP00000479968.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000538 AC: 1 AN: 185714 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 98556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420540 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 702478

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000260

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CYFIP2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 31 of the CYFIP2 protein (p.Pro31Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;.;.;T;T;T;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	L;L;.;.;.;.;.;.;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.5	.;.;D;.;N;.;.;.;.
REVEL	Benign	0.097
Sift	Uncertain	0.028	.;.;D;.;T;.;.;.;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T
Polyphen		0.97	D;P;P;.;P;.;.;.;P
Vest4		0.54
MutPred		0.44		Loss of catalytic residue at P31 (P = 0.0362);Loss of catalytic residue at P31 (P = 0.0362);Loss of catalytic residue at P31 (P = 0.0362);Loss of catalytic residue at P31 (P = 0.0362);Loss of catalytic residue at P31 (P = 0.0362);Loss of catalytic residue at P31 (P = 0.0362);Loss of catalytic residue at P31 (P = 0.0362);Loss of catalytic residue at P31 (P = 0.0362);Loss of catalytic residue at P31 (P = 0.0362);
MVP		0.31
MPC		1.3
ClinPred		0.71	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.98

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: rs1461152506; hg19: chr5-156712462;