rs115735611

Positions:

• chr2-232791426-A-C
• chr2-232791426-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001103146.3(GIGYF2):​c.1262A>C​(p.Lys421Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K421R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GIGYF2 NM_001103146.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99

Genes affected

GIGYF2 (HGNC:11960): (GRB10 interacting GYF protein 2) This gene contains CAG trinucleotide repeats and encodes a protein containing several stretches of polyglutamine residues. The encoded protein may be involved in the regulation of tyrosine kinase receptor signaling. This gene is located in a chromosomal region that was genetically linked to Parkinson disease type 11, and mutations in this gene were thought to be causative for this disease. However, more recent studies in different populations have been unable to replicate this association. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13500673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIGYF2	NM_001103146.3	c.1262A>C	p.Lys421Thr	missense_variant	12/29	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9	c.1262A>C	p.Lys421Thr	missense_variant	12/29	1	NM_001103146.3	ENSP00000362664	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461642 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	.;T;.;T;T;.;.;T
Eigen	Benign	-0.025
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;.;.;T;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	0.93	N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.60	.;N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.019	.;D;D;D;D;D;D;D
Sift4G	Benign	0.50	T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;.;B;.;.;.;.
Vest4		0.21
MutPred		0.22		.;Loss of ubiquitination at K421 (P = 0.0027);.;Loss of ubiquitination at K421 (P = 0.0027);.;.;.;.;
MVP		0.54
MPC		0.40
ClinPred		0.22	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.069
gMVP		0.32

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: rs115735611; hg19: chr2-233656136;