rs111562095

Variant names:

• chr19-45361788-A-C
• rs111562095
• NM_000400.4:c.1119-146T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-45361788-A-C
• chr19-45361788-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000400.4(ERCC2):​c.1119-146T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 703,866 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (47 hom., cov: 33)
  • Exomes 𝑓: 0.023 (204 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.0230
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-45361788-A-C is Benign according to our data. Variant chr19-45361788-A-C is described in ClinVar as Benign. ClinVar VariationId is 135531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0195 (2964/152146) while in subpopulation NFE AF = 0.0261 (1777/67990). AF 95% confidence interval is 0.0251. There are 47 homozygotes in GnomAd4. There are 1442 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AR gene

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.1119-146T>G		intron	N/A	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.1047-146T>G		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.1041-146T>G		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.1119-146T>G		intron	N/A	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.1119-146T>G		intron	N/A	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.1047-146T>G		intron	N/A	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2963 AN: 152028 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.00500

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0514

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0261

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0211 AC: 3165 AN: 149676 AF XY: 0.0204

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0636

Gnomad EAS exome AF: 0.0000863

Gnomad FIN exome AF: 0.0530

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0234 AC: 12914 AN: 551720 Hom.: 204 Cov.: 5 AF XY: 0.0223 AC XY: 6661 AN XY: 298342

African (AFR) AF: 0.00368 AC: 58 AN: 15760

American (AMR) AF: 0.0121 AC: 414 AN: 34212

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 1156 AN: 19370

East Asian (EAS) AF: 0.0000317 AC: 1 AN: 31560

South Asian (SAS) AF: 0.00517 AC: 323 AN: 62426

European-Finnish (FIN) AF: 0.0446 AC: 1761 AN: 39486

Middle Eastern (MID) AF: 0.0192 AC: 77 AN: 4018

European-Non Finnish (NFE) AF: 0.0267 AC: 8395 AN: 314990

Other (OTH) AF: 0.0244 AC: 729 AN: 29898

GnomAD4 genome AF: 0.0195 AC: 2964 AN: 152146 Hom.: 47 Cov.: 33 AF XY: 0.0194 AC XY: 1442 AN XY: 74380

African (AFR) AF: 0.00499 AC: 207 AN: 41506

American (AMR) AF: 0.0119 AC: 182 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 188 AN: 3472

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

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4826

European-Finnish (FIN) AF: 0.0514 AC: 544 AN: 10580

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0261 AC: 1777 AN: 67990

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.0205 Hom.: 10

Bravo AF: 0.0166

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.64
PhyloP100		0.023
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: rs111562095; hg19: chr19-45865046; COSMIC: COSV55539928; COSMIC: COSV55539928;