chr19-45368348-T-C

Variant names:

• chr19-45368348-T-C
• rs1618536
• NM_000400.4:c.360+282A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000400.4(ERCC2):​c.360+282A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 151,992 control chromosomes in the GnomAD database, including 32,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.64 (32685 hom., cov: 31)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.20
• Publications: 27 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-45368348-T-C is Benign according to our data. Variant chr19-45368348-T-C is described in ClinVar as Benign. ClinVar VariationId is 1294042.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.862 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	NM_000400.4	MANE Select	c.360+282A>G		intron	N/A	NP_000391.1
	ERCC2	NM_001440355.1		c.288+282A>G		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.282+282A>G		intron	N/A	NP_001427285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.360+282A>G		intron	N/A	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.360+282A>G		intron	N/A	ENSP00000375808.4
	ERCC2	ENST00000391941.6	TSL:1	c.288+282A>G		intron	N/A	ENSP00000375805.2

Frequencies

GnomAD3 genomes AF: 0.639 AC: 97028 AN: 151874 Hom.: 32634 Cov.: 31

Gnomad AFR AF: 0.870

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.618

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.594

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

GnomAD4 genome AF: 0.639 AC: 97131 AN: 151992 Hom.: 32685 Cov.: 31 AF XY: 0.636 AC XY: 47232 AN XY: 74280

African (AFR) AF: 0.870 AC: 36087 AN: 41494

American (AMR) AF: 0.527 AC: 8026 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2028 AN: 3472

East Asian (EAS) AF: 0.500 AC: 2584 AN: 5168

South Asian (SAS) AF: 0.588 AC: 2830 AN: 4810

European-Finnish (FIN) AF: 0.591 AC: 6238 AN: 10558

Middle Eastern (MID) AF: 0.623 AC: 182 AN: 292

European-Non Finnish (NFE) AF: 0.550 AC: 37389 AN: 67954

Other (OTH) AF: 0.594 AC: 1248 AN: 2102

Alfa AF: 0.576 Hom.: 47813

Bravo AF: 0.646

Asia WGS AF: 0.566 AC: 1971 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.29
DANN	Benign	0.51
PhyloP100		-1.2
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: rs1618536; hg19: chr19-45871606;