rs50871

Variant names:

• chr19-45359257-C-A
• rs50871
• NM_000400.4:c.1238-1558G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-45359257-C-A
• chr19-45359257-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000400.4(ERCC2):​c.1238-1558G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 151,878 control chromosomes in the GnomAD database, including 33,022 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 0.64 (33022 hom., cov: 31)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.793
• Publications: 45 publications found

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ERCC2 Gene-Disease associations (from GenCC):

• cerebrooculofacioskeletal syndrome 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000400.4. 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
	ERCC2	NM_000400.4	MANE Select	c.1238-1558G>T		intron	N/A	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.1166-1558G>T		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.1160-1558G>T		intron	N/A	NP_001427285.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.1238-1558G>T		intron	N/A	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.1238-1558G>T		intron	N/A	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.1166-1558G>T		intron	N/A	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes AF: 0.639 AC: 96967 AN: 151760 Hom.: 32975 Cov.: 31

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.639 AC: 97074 AN: 151878 Hom.: 33022 Cov.: 31 AF XY: 0.642 AC XY: 47636 AN XY: 74186

African (AFR) AF: 0.881 AC: 36545 AN: 41472

American (AMR) AF: 0.591 AC: 9004 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2022 AN: 3466

East Asian (EAS) AF: 0.731 AC: 3751 AN: 5132

South Asian (SAS) AF: 0.680 AC: 3274 AN: 4814

European-Finnish (FIN) AF: 0.545 AC: 5724 AN: 10494

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.515 AC: 34996 AN: 67942

Other (OTH) AF: 0.599 AC: 1265 AN: 2112

Alfa AF: 0.549 Hom.: 51214

Bravo AF: 0.648

Asia WGS AF: 0.730 AC: 2539 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.13
DANN	Benign	0.35
PhyloP100		-0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.99
Mutation Taster		=100/0	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: rs50871; hg19: chr19-45862515;