2-232844096-A-C

Variant names:

• chr2-232844096-A-C
• rs3816334
• NM_001103146.3:c.2940A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001103146.3(GIGYF2):​c.2940A>C​(p.Gln980His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q980Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GIGYF2 NM_001103146.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 0 publications found

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]

GIGYF2 Gene-Disease associations (from GenCC):

• Parkinson disease 11, autosomal dominant, susceptibility to

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3037076).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103146.3. 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
	GIGYF2	NM_001103146.3	MANE Select	c.2940A>C	p.Gln980His	missense	Exon 24 of 29	NP_001096616.1	Q6Y7W6-1
	GIGYF2	NM_001103147.2		c.3003A>C	p.Gln1001His	missense	Exon 26 of 31	NP_001096617.1	Q6Y7W6-3
	GIGYF2	NM_015575.4		c.2940A>C	p.Gln980His	missense	Exon 26 of 31	NP_056390.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.2940A>C	p.Gln980His	missense	Exon 24 of 29	ENSP00000362664.5	Q6Y7W6-1
	GIGYF2	ENST00000409451.7	TSL:1	c.3003A>C	p.Gln1001His	missense	Exon 26 of 31	ENSP00000387170.3	Q6Y7W6-3
	GIGYF2	ENST00000409547.5	TSL:1	c.2940A>C	p.Gln980His	missense	Exon 26 of 31	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450466 Hom.: 0 Cov.: 38 AF XY: 0.00000139 AC XY: 1 AN XY: 721272

African (AFR) AF: 0.0000301 AC: 1 AN: 33222

American (AMR) AF: 0.00 AC: 0 AN: 44106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 85464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103582

Other (OTH) AF: 0.00 AC: 0 AN: 59942

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.36	T
PhyloP100		1.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.0020	B
Vest4		0.32
MutPred		0.14		Loss of helix (P = 0.079)
MVP		0.71
MPC		0.29
ClinPred		0.21	T
GERP RS		2.3
Varity_R		0.17
gMVP		0.61
Mutation Taster		=56/44	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: rs3816334; hg19: chr2-233708806;