Genetic Variant CCDC69:c.48+8682A>G (chr5-151215241-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015621.3(CCDC69):c.48+8682A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,024 control chromosomes in the GnomAD database, including 7,182 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7182 hom., cov: 32)

Consequence

CCDC69
NM_015621.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.211

Publications

15 publications found

Variant links:

Genes affected

CCDC69 (HGNC:24487): (coiled-coil domain containing 69) Predicted to enable microtubule binding activity. Involved in spindle midzone assembly. Located in spindle midzone. [provided by Alliance of Genome Resources, Apr 2022]

CCDC69 links:

GM2A (HGNC:4367): (ganglioside GM2 activator) This gene encodes a small glycolipid transport protein which acts as a substrate specific co-factor for the lysosomal enzyme beta-hexosaminidase A. Beta-hexosaminidase A, together with GM2 ganglioside activator, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene result in GM2-gangliosidosis type AB or the AB variant of Tay-Sachs disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

GM2A Gene-Disease associations (from GenCC):

Tay-Sachs disease AB variant
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen

GM2A links:

LOC105378230 (HGNC:):

LOC105378230 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC69	NM_015621.3 link	c.48+8682A>G		intron_variant	Intron 1 of 8	ENST00000355417.7	NP_056436.2	A6NI79Q7L2X4
LOC105378230	NR_160730.1 link	n.257+2352T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC69	ENST00000355417.7 link	c.48+8682A>G	intron_variant	Intron 1 of 8	1	NM_015621.3	ENSP00000347586.2	A6NI79
CCDC69	ENST00000521308.5 link	n.171+8682A>G	intron_variant	Intron 1 of 7	1
GM2A	ENST00000523466.5 link	c.126+2352T>C	intron_variant	Intron 2 of 3	3		ENSP00000429100.1	E5RJD0

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46117

AN:

151908

Hom.:

7171

Cov.:

show subpopulations

Gnomad AFR

AF:

0.306

Gnomad AMI

AF:

0.313

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.366

Gnomad EAS

AF:

0.197

Gnomad SAS

AF:

0.275

Gnomad FIN

AF:

0.264

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.325

Gnomad OTH

AF:

0.292

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.304

AC:

46161

AN:

152024

Hom.:

7182

Cov.:

AF XY:

0.300

AC XY:

22286

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.306

AC:

12704

AN:

41450

American (AMR)

AF:

0.256

AC:

3908

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

1271

AN:

3470

East Asian (EAS)

AF:

0.198

AC:

1021

AN:

5168

South Asian (SAS)

AF:

0.274

AC:

1322

AN:

4824

European-Finnish (FIN)

AF:

0.264

AC:

2791

AN:

10582

Middle Eastern (MID)

AF:

0.483

AC:

141

AN:

292

European-Non Finnish (NFE)

AF:

0.325

AC:

22092

AN:

67942

Other (OTH)

AF:

0.297

AC:

626

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1642

3285

4927

6570

8212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

470

940

1410

1880

2350

<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:

0.315

Hom.:

11933

Bravo

AF:

0.303

Asia WGS

AF:

0.258

AC:

896

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.41

(source)

DANN

Benign

0.32

PhyloP100

-0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over