rs2228001

Variant names:

• chr3-14145949-G-T
• rs2228001
• NM_004628.5:c.2815C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-14145949-G-T
• chr3-14145949-G-A
• chr3-14145949-G-C

Variant summary

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

The NM_004628.5(XPC):​c.2815C>A​(p.Gln939Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,602,772 control chromosomes in the GnomAD database, including 302,541 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32194 hom., cov: 31)
  • Exomes 𝑓: 0.61 (270347 hom.)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.83
• Publications: 426 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]

ENSG00000268279 (HGNC:):

XPC-AS1 (HGNC:55014): (XPC antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.3247075E-6).
• BP6: Variant 3-14145949-G-T is Benign according to our data. Variant chr3-14145949-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 190215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 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.2815C>A	p.Gln939Lys	missense	Exon 16 of 16	NP_004619.3
	XPC	NM_001354727.2		c.2809C>A	p.Gln937Lys	missense	Exon 16 of 16	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.2797C>A	p.Gln933Lys	missense	Exon 16 of 16	NP_001341658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.2815C>A	p.Gln939Lys	missense	Exon 16 of 16	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*2268C>A		non_coding_transcript_exon	Exon 15 of 15	ENSP00000424548.1	Q01831-3
	XPC	ENST00000476581.6	TSL:1	n.*2268C>A		3_prime_UTR	Exon 15 of 15	ENSP00000424548.1	Q01831-3

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98325 AN: 151840 Hom.: 32144 Cov.: 31

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.699

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.645

GnomAD2 exomes AF: 0.633 AC: 156744 AN: 247442 AF XY: 0.627

Gnomad AFR exome AF: 0.730

Gnomad AMR exome AF: 0.706

Gnomad ASJ exome AF: 0.528

Gnomad EAS exome AF: 0.639

Gnomad FIN exome AF: 0.698

Gnomad NFE exome AF: 0.592

Gnomad OTH exome AF: 0.604

GnomAD4 exome AF: 0.609 AC: 883010 AN: 1450814 Hom.: 270347 Cov.: 56 AF XY: 0.607 AC XY: 437096 AN XY: 719594

African (AFR) AF: 0.729 AC: 24150 AN: 33134

American (AMR) AF: 0.703 AC: 31092 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 13687 AN: 25912

East Asian (EAS) AF: 0.617 AC: 24298 AN: 39386

South Asian (SAS) AF: 0.646 AC: 55442 AN: 85822

European-Finnish (FIN) AF: 0.692 AC: 36722 AN: 53048

Middle Eastern (MID) AF: 0.456 AC: 2550 AN: 5592

European-Non Finnish (NFE) AF: 0.597 AC: 658975 AN: 1103878

Other (OTH) AF: 0.603 AC: 36094 AN: 59824

GnomAD4 genome AF: 0.648 AC: 98450 AN: 151958 Hom.: 32194 Cov.: 31 AF XY: 0.653 AC XY: 48518 AN XY: 74250

African (AFR) AF: 0.726 AC: 30095 AN: 41434

American (AMR) AF: 0.671 AC: 10255 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1848 AN: 3468

East Asian (EAS) AF: 0.637 AC: 3275 AN: 5142

South Asian (SAS) AF: 0.658 AC: 3168 AN: 4812

European-Finnish (FIN) AF: 0.699 AC: 7401 AN: 10582

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40290 AN: 67920

Other (OTH) AF: 0.648 AC: 1366 AN: 2108

Alfa AF: 0.608 Hom.: 97106

Bravo AF: 0.649

TwinsUK AF: 0.593 AC: 2200

ALSPAC AF: 0.604 AC: 2326

ESP6500AA AF: 0.730 AC: 2775

ESP6500EA AF: 0.601 AC: 4949

ExAC AF: 0.631 AC: 76275

Asia WGS AF: 0.681 AC: 2368 AN: 3478

EpiCase AF: 0.570

EpiControl AF: 0.573

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Xeroderma pigmentosum, group C (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Xeroderma pigmentosum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.5	N
PhyloP100		2.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.095
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.15
ClinPred		0.0028	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.080
Mutation Taster		=98/2	polymorphism (auto)

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: rs2228001; hg19: chr3-14187449; COSMIC: COSV53207797; COSMIC: COSV53207797;