rs2228002

Variant names:

• chr3-14170550-C-T
• rs2228002
• NM_004628.5:c.300G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004628.5(XPC):​c.300G>A​(p.Arg100Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,608,880 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (120 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (150 hom.)
• Consequence: XPC NM_004628.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.006728
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.410
• Publications: 5 publications found

Genes affected

XPC (HGNC:12816): (XPC complex subunit, DNA damage recognition and repair factor) The protein encoded by this gene is a key component of the XPC complex, which plays an important role in the early steps of global genome nucleotide excision repair (NER). The encoded protein is important for damage sensing and DNA binding, and shows a preference for single-stranded DNA. Mutations in this gene or some other NER components can result in Xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

XPC Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Genomics England PanelApp, ClinGen, G2P
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-14170550-C-T is Benign according to our data. Variant chr3-14170550-C-T is described in ClinVar as Benign. ClinVar VariationId is 135476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004628.5. 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
	XPC	NM_004628.5	MANE Select	c.300G>A	p.Arg100Arg	splice_region synonymous	Exon 3 of 16	NP_004619.3
	XPC	NM_001354726.2		c.-156G>A		splice_region	Exon 3 of 15	NP_001341655.1
	XPC	NM_001354727.2		c.300G>A	p.Arg100Arg	splice_region synonymous	Exon 3 of 16	NP_001341656.1	A0ABB0MVJ4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.300G>A	p.Arg100Arg	splice_region synonymous	Exon 3 of 16	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.300G>A		splice_region non_coding_transcript_exon	Exon 3 of 15	ENSP00000424548.1	Q01831-3
	XPC	ENST00000850575.1		c.300G>A	p.Arg100Arg	splice_region synonymous	Exon 3 of 16	ENSP00000520865.1	A0ABB0MVJ4

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3341 AN: 152120 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.0758

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00550 AC: 1353 AN: 245992 AF XY: 0.00392

Gnomad AFR exome AF: 0.0790

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00228 AC: 3317 AN: 1456642 Hom.: 150 Cov.: 29 AF XY: 0.00192 AC XY: 1392 AN XY: 724398

African (AFR) AF: 0.0825 AC: 2745 AN: 33286

American (AMR) AF: 0.00380 AC: 168 AN: 44170

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25994

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39568

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5744

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1108954

Other (OTH) AF: 0.00454 AC: 273 AN: 60148

GnomAD4 genome AF: 0.0219 AC: 3340 AN: 152238 Hom.: 120 Cov.: 32 AF XY: 0.0214 AC XY: 1595 AN XY: 74442

African (AFR) AF: 0.0755 AC: 3136 AN: 41518

American (AMR) AF: 0.00974 AC: 149 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68012

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.00920 Hom.: 103

Bravo AF: 0.0250

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Xeroderma pigmentosum, group C (3)
-	-	2	not specified (3)
-	-	1	Xeroderma pigmentosum group A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.54
PhyloP100		0.41
Mutation Taster		=71/29	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0067
dbscSNV1_RF	Benign	0.044
SpliceAI score (max)		0.050		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: rs2228002; hg19: chr3-14212050; COSMIC: COSV104532508;