19-45351802-C-G

Variant names:

• chr19-45351802-C-G
• rs1799790
• ENST00000391944.8:c.*107G>C

Variant summary

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

The ENST00000391945.10(ERCC2):​c.2191-81G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,239,318 control chromosomes in the GnomAD database, including 75,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7368 hom., cov: 32)
  • Exomes 𝑓: 0.34 (67936 hom.)
• Consequence: ERCC2 ENST00000391945.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08
• Publications: 6 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, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), 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=-0.89).
• BP6: Variant 19-45351802-C-G is Benign according to our data. Variant chr19-45351802-C-G is described in ClinVar as Benign. ClinVar VariationId is 1182968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000391945.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	NM_000400.4	MANE Select	c.2191-81G>C		intron	N/A	NP_000391.1
	ERCC2	NM_001440355.1		c.2119-81G>C		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.2113-81G>C		intron	N/A	NP_001427285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391944.8	TSL:1	c.*107G>C		3_prime_UTR	Exon 22 of 22	ENSP00000375808.4
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.2191-81G>C		intron	N/A	ENSP00000375809.4
	ERCC2	ENST00000684407.1		c.2068-81G>C		intron	N/A	ENSP00000507775.1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43104 AN: 152098 Hom.: 7369 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.0734

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.295

GnomAD4 exome AF: 0.345 AC: 374602 AN: 1087102 Hom.: 67936 AF XY: 0.348 AC XY: 192574 AN XY: 554082

African (AFR) AF: 0.110 AC: 2884 AN: 26306

American (AMR) AF: 0.191 AC: 8067 AN: 42260

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 9037 AN: 22592

East Asian (EAS) AF: 0.0548 AC: 2078 AN: 37934

South Asian (SAS) AF: 0.368 AC: 28209 AN: 76632

European-Finnish (FIN) AF: 0.411 AC: 19283 AN: 46928

Middle Eastern (MID) AF: 0.384 AC: 1685 AN: 4390

European-Non Finnish (NFE) AF: 0.368 AC: 287496 AN: 782300

Other (OTH) AF: 0.332 AC: 15863 AN: 47760

GnomAD4 genome AF: 0.283 AC: 43102 AN: 152216 Hom.: 7368 Cov.: 32 AF XY: 0.285 AC XY: 21193 AN XY: 74416

African (AFR) AF: 0.122 AC: 5050 AN: 41536

American (AMR) AF: 0.241 AC: 3677 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1361 AN: 3470

East Asian (EAS) AF: 0.0730 AC: 378 AN: 5176

South Asian (SAS) AF: 0.362 AC: 1746 AN: 4826

European-Finnish (FIN) AF: 0.418 AC: 4429 AN: 10600

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.373 AC: 25356 AN: 68006

Other (OTH) AF: 0.291 AC: 615 AN: 2112

Alfa AF: 0.205 Hom.: 497

Bravo AF: 0.258

Asia WGS AF: 0.179 AC: 627 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.45
DANN	Benign	0.43
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1799790; hg19: chr19-45855060;