NM_000400.4:c.1119-116C>G

Variant names:

• chr19-45361758-G-C
• rs73559309
• NM_000400.4:c.1119-116C>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.1119-116C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 795,316 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (93 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (47 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -1.53
• Publications: 1 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=-0.93).
• BP6: Variant 19-45361758-G-C is Benign according to our data. Variant chr19-45361758-G-C is described in ClinVar as Benign. ClinVar VariationId is 135530.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 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.1119-116C>G		intron	N/A	NP_000391.1
	ERCC2	NM_001440355.1		c.1047-116C>G		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.1041-116C>G		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.1119-116C>G		intron	N/A	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.1119-116C>G		intron	N/A	ENSP00000375808.4
	ERCC2	ENST00000391941.6	TSL:1	c.1047-116C>G		intron	N/A	ENSP00000375805.2

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2875 AN: 152140 Hom.: 93 Cov.: 33

Gnomad AFR AF: 0.0655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00512 AC: 934 AN: 182260 AF XY: 0.00373

Gnomad AFR exome AF: 0.0723

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.000225

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000219

Gnomad OTH exome AF: 0.00303

GnomAD4 exome AF: 0.00257 AC: 1652 AN: 643058 Hom.: 47 Cov.: 8 AF XY: 0.00210 AC XY: 724 AN XY: 344654

African (AFR) AF: 0.0673 AC: 1196 AN: 17768

American (AMR) AF: 0.00422 AC: 153 AN: 36226

Ashkenazi Jewish (ASJ) AF: 0.000198 AC: 4 AN: 20222

East Asian (EAS) AF: 0.00 AC: 0 AN: 33492

South Asian (SAS) AF: 0.000121 AC: 8 AN: 66172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45822

Middle Eastern (MID) AF: 0.00168 AC: 7 AN: 4162

European-Non Finnish (NFE) AF: 0.000184 AC: 71 AN: 386182

Other (OTH) AF: 0.00645 AC: 213 AN: 33012

GnomAD4 genome AF: 0.0189 AC: 2885 AN: 152258 Hom.: 93 Cov.: 33 AF XY: 0.0178 AC XY: 1328 AN XY: 74454

African (AFR) AF: 0.0656 AC: 2724 AN: 41528

American (AMR) AF: 0.00706 AC: 108 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68026

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0114 Hom.: 10

Bravo AF: 0.0226

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0060
DANN	Benign	0.44
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs73559309; hg19: chr19-45865016;