11-47238768-A-G

Variant names:

• chr11-47238768-A-G
• rs901746
• NM_000107.3:c.1235-32A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000107.3(DDB2):​c.1235-32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,610,664 control chromosomes in the GnomAD database, including 103,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13973 hom., cov: 30)
  • Exomes 𝑓: 0.34 (89648 hom.)
• Consequence: DDB2 NM_000107.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.552
• Publications: 43 publications found

Genes affected

DDB2 (HGNC:2718): (damage specific DNA binding protein 2) This gene encodes a protein that is necessary for the repair of ultraviolet light-damaged DNA. This protein is the smaller subunit of a heterodimeric protein complex that participates in nucleotide excision repair, and this complex mediates the ubiquitylation of histones H3 and H4, which facilitates the cellular response to DNA damage. This subunit appears to be required for DNA binding. Mutations in this gene cause xeroderma pigmentosum complementation group E, a recessive disease that is characterized by an increased sensitivity to UV light and a high predisposition for skin cancer development, in some cases accompanied by neurological abnormalities. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ACP2 (HGNC:123): (acid phosphatase 2, lysosomal) The protein encoded by this gene belongs to the histidine acid phosphatase family, which hydrolyze orthophosphoric monoesters to alcohol and phosphate. This protein is localized to the lysosomal membrane, and is chemically and genetically distinct from the red cell acid phosphatase. Mice lacking this gene showed multiple defects, including bone structure alterations, lysosomal storage defects, and an increased tendency towards seizures. An enzymatically-inactive allele of this gene in mice showed severe growth retardation, hair-follicle abnormalities, and an ataxia-like phenotype. Alternatively spliced transcript variants have been found for this gene. A C-terminally extended isoform is also predicted to be produced by the use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism. [provided by RefSeq, Oct 2017]

ACP2 Gene-Disease associations (from GenCC):

• lysosomal acid phosphatase deficiency

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-47238768-A-G is Benign according to our data. Variant chr11-47238768-A-G is described in ClinVar as Benign. ClinVar VariationId is 1182792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000107.3. 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
	DDB2	NM_000107.3	MANE Select	c.1235-32A>G		intron	N/A	NP_000098.1	Q92466-1
	DDB2	NM_001399874.1		c.1235-32A>G		intron	N/A	NP_001386803.1	Q92466-1
	DDB2	NM_001399875.1		c.1235-32A>G		intron	N/A	NP_001386804.1	Q92466-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDB2	ENST00000256996.9	TSL:1 MANE Select	c.1235-32A>G		intron	N/A	ENSP00000256996.4	Q92466-1
	DDB2	ENST00000378603.7	TSL:1	c.1043-32A>G		intron	N/A	ENSP00000367866.3	Q92466-4
	DDB2	ENST00000378600.7	TSL:1	c.668-32A>G		intron	N/A	ENSP00000367863.3	Q92466-2

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61569 AN: 151438 Hom.: 13959 Cov.: 30

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.750

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.344

GnomAD2 exomes AF: 0.397 AC: 98939 AN: 249526 AF XY: 0.387

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.758

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.336 AC: 490310 AN: 1459106 Hom.: 89648 Cov.: 30 AF XY: 0.337 AC XY: 244969 AN XY: 726006

African (AFR) AF: 0.574 AC: 19204 AN: 33444

American (AMR) AF: 0.429 AC: 19157 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5698 AN: 26096

East Asian (EAS) AF: 0.742 AC: 29443 AN: 39670

South Asian (SAS) AF: 0.461 AC: 39758 AN: 86214

European-Finnish (FIN) AF: 0.409 AC: 21726 AN: 53108

Middle Eastern (MID) AF: 0.273 AC: 1564 AN: 5730

European-Non Finnish (NFE) AF: 0.300 AC: 332917 AN: 1109904

Other (OTH) AF: 0.346 AC: 20843 AN: 60302

GnomAD4 genome AF: 0.407 AC: 61617 AN: 151558 Hom.: 13973 Cov.: 30 AF XY: 0.416 AC XY: 30798 AN XY: 74016

African (AFR) AF: 0.570 AC: 23527 AN: 41298

American (AMR) AF: 0.365 AC: 5552 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 778 AN: 3470

East Asian (EAS) AF: 0.750 AC: 3832 AN: 5108

South Asian (SAS) AF: 0.467 AC: 2243 AN: 4808

European-Finnish (FIN) AF: 0.427 AC: 4476 AN: 10480

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.299 AC: 20296 AN: 67874

Other (OTH) AF: 0.340 AC: 714 AN: 2100

Alfa AF: 0.330 Hom.: 13277

Bravo AF: 0.408

Asia WGS AF: 0.550 AC: 1909 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Xeroderma pigmentosum, group E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.53
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs901746; hg19: chr11-47260319; COSMIC: COSV57036879;