19-45370684-G-C

Variant names:

• chr19-45370684-G-C
• rs3810366
• ENST00000391941.6:c.-519C>G

Variant summary

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

The ENST00000391941.6(ERCC2):​c.-519C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 834,764 control chromosomes in the GnomAD database, including 98,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (25874 hom., cov: 31)
  • Exomes 𝑓: 0.46 (73002 hom.)
• Consequence: ERCC2 ENST00000391941.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0260
• Publications: 36 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=-0.75).
• BP6: Variant 19-45370684-G-C is Benign according to our data. Variant chr19-45370684-G-C is described in ClinVar as Benign. ClinVar VariationId is 1221224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.-144C>G		upstream_gene_variant		ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.-144C>G		upstream_gene_variant		1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84183 AN: 151986 Hom.: 25824 Cov.: 31

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.518

GnomAD4 exome AF: 0.457 AC: 311674 AN: 682660 Hom.: 73002 Cov.: 9 AF XY: 0.457 AC XY: 162929 AN XY: 356410

African (AFR) AF: 0.848 AC: 15246 AN: 17978

American (AMR) AF: 0.469 AC: 15402 AN: 32872

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 9570 AN: 19980

East Asian (EAS) AF: 0.457 AC: 14576 AN: 31904

South Asian (SAS) AF: 0.493 AC: 31735 AN: 64370

European-Finnish (FIN) AF: 0.425 AC: 14013 AN: 32984

Middle Eastern (MID) AF: 0.484 AC: 1991 AN: 4112

European-Non Finnish (NFE) AF: 0.434 AC: 192791 AN: 444232

Other (OTH) AF: 0.478 AC: 16350 AN: 34228

GnomAD4 genome AF: 0.554 AC: 84289 AN: 152104 Hom.: 25874 Cov.: 31 AF XY: 0.550 AC XY: 40858 AN XY: 74334

African (AFR) AF: 0.845 AC: 35088 AN: 41512

American (AMR) AF: 0.468 AC: 7140 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1643 AN: 3472

East Asian (EAS) AF: 0.465 AC: 2404 AN: 5168

South Asian (SAS) AF: 0.471 AC: 2271 AN: 4818

European-Finnish (FIN) AF: 0.424 AC: 4485 AN: 10590

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29523 AN: 67952

Other (OTH) AF: 0.519 AC: 1098 AN: 2116

Alfa AF: 0.303 Hom.: 651

Bravo AF: 0.574

Asia WGS AF: 0.497 AC: 1731 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.8
DANN	Benign	0.39
PhyloP100		0.026
PromoterAI		-0.028	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3810366; hg19: chr19-45873942; COSMIC: COSV55543445;