Genetic Variant NM_001103146.3:c.268-10_268-6delTTTTT (chr2-232756197-CTTTTT-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001103146.3(GIGYF2):c.268-10_268-6delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 705,878 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0027 ( 0 hom. )

Consequence

GIGYF2
NM_001103146.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.60

Publications

0 publications found

Variant links:

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

GIGYF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 36 AD,Unknown gene.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GIGYF2	NM_001103146.3	MANE Select	c.268-10_268-6delTTTTT	splice_region intron	N/A	NP_001096616.1	Q6Y7W6-1
GIGYF2	NM_001103147.2		c.268-10_268-6delTTTTT	splice_region intron	N/A	NP_001096617.1	Q6Y7W6-3
GIGYF2	NM_015575.4		c.268-10_268-6delTTTTT	splice_region intron	N/A	NP_056390.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.268-25_268-21delTTTTT	intron	N/A	ENSP00000362664.5	Q6Y7W6-1
GIGYF2	ENST00000409451.7	TSL:1	c.268-25_268-21delTTTTT	intron	N/A	ENSP00000387170.3	Q6Y7W6-3
GIGYF2	ENST00000409547.5	TSL:1	c.268-25_268-21delTTTTT	intron	N/A	ENSP00000386537.1	Q6Y7W6-1

Frequencies

GnomAD3 genomes

AF:

0.000350

AC:

AN:

102712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000307

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000533

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00268

AC:

1618

AN:

603166

Hom.:

AF XY:

0.00246

AC XY:

788

AN XY:

319878

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00319

AC:

AN:

14742

American (AMR)

AF:

0.00227

AC:

AN:

25596

Ashkenazi Jewish (ASJ)

AF:

0.00282

AC:

AN:

15958

East Asian (EAS)

AF:

0.00235

AC:

AN:

31038

South Asian (SAS)

AF:

0.00133

AC:

AN:

48090

European-Finnish (FIN)

AF:

0.00180

AC:

AN:

36658

Middle Eastern (MID)

AF:

0.00400

AC:

AN:

2248

European-Non Finnish (NFE)

AF:

0.00295

AC:

1178

AN:

399340

Other (OTH)

AF:

0.00264

AC:

AN:

29496

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.295

Heterozygous variant carriers

165

330

494

659

824

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000350

AC:

AN:

102712

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

AN XY:

47572

show subpopulations

African (AFR)

AF:

0.000307

AC:

AN:

26026

American (AMR)

AF:

0.00

AC:

AN:

8736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2792

East Asian (EAS)

AF:

0.00

AC:

AN:

3762

South Asian (SAS)

AF:

0.00

AC:

AN:

2920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

172

European-Non Finnish (NFE)

AF:

0.000533

AC:

AN:

52578

Other (OTH)

AF:

0.00

AC:

AN:

1318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over