19-45362432-C-T

Variant names:

• chr19-45362432-C-T
• rs238404
• NM_000400.4:c.1119-790G>A

Variant summary

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

The NM_000400.4(ERCC2):​c.1119-790G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 152,094 control chromosomes in the GnomAD database, including 32,072 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 0.63 (32072 hom., cov: 33)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 12 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.855 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.1119-790G>A		intron	N/A	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.1047-790G>A		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.1041-790G>A		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.1119-790G>A		intron	N/A	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.1119-790G>A		intron	N/A	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.1047-790G>A		intron	N/A	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96141 AN: 151976 Hom.: 32025 Cov.: 33

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.589

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

GnomAD4 genome AF: 0.633 AC: 96239 AN: 152094 Hom.: 32072 Cov.: 33 AF XY: 0.629 AC XY: 46753 AN XY: 74316

African (AFR) AF: 0.862 AC: 35807 AN: 41534

American (AMR) AF: 0.526 AC: 8031 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2027 AN: 3472

East Asian (EAS) AF: 0.499 AC: 2571 AN: 5156

South Asian (SAS) AF: 0.587 AC: 2829 AN: 4818

European-Finnish (FIN) AF: 0.570 AC: 6018 AN: 10566

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 37018 AN: 67956

Other (OTH) AF: 0.589 AC: 1242 AN: 2110

Alfa AF: 0.522 Hom.: 4157

Bravo AF: 0.640

Asia WGS AF: 0.562 AC: 1955 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.039
DANN	Benign	0.49
PhyloP100		-1.3
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8
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: rs238404; hg19: chr19-45865690;