chr19-45352004-G-T

Variant names:

• chr19-45352004-G-T
• rs238418
• ENST00000391944.8:c.2395C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000391944.8(ERCC2):​c.2395C>A​(p.Arg799Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 152,048 control chromosomes in the GnomAD database, including 23,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.52 (23713 hom., cov: 32)
• Consequence: ERCC2 ENST00000391944.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.212
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 19-45352004-G-T is Benign according to our data. Variant chr19-45352004-G-T is described in ClinVar as Benign. ClinVar VariationId is 1230280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.212 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000391944.8. 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.2190+205C>A		intron	N/A	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.2118+205C>A		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.2112+205C>A		intron	N/A	NP_001427285.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391944.8	TSL:1	c.2395C>A	p.Arg799Arg	synonymous	Exon 22 of 22	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.2190+205C>A		intron	N/A	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000891927.1		c.2286+205C>A		intron	N/A	ENSP00000561986.1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78652 AN: 151930 Hom.: 23662 Cov.: 32

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.477

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

GnomAD4 genome AF: 0.518 AC: 78749 AN: 152048 Hom.: 23713 Cov.: 32 AF XY: 0.517 AC XY: 38389 AN XY: 74320

African (AFR) AF: 0.845 AC: 35081 AN: 41494

American (AMR) AF: 0.424 AC: 6470 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1452 AN: 3470

East Asian (EAS) AF: 0.298 AC: 1538 AN: 5156

South Asian (SAS) AF: 0.417 AC: 2009 AN: 4822

European-Finnish (FIN) AF: 0.466 AC: 4915 AN: 10558

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25789 AN: 67968

Other (OTH) AF: 0.470 AC: 989 AN: 2104

Alfa AF: 0.281 Hom.: 611

Bravo AF: 0.528

ClinVar

ClinVar submissions

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	-0.95
CADD	Benign	0.38
DANN	Benign	0.57
PhyloP100		-0.21
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: rs238418; hg19: chr19-45855262;