NM_000400.4:c.949+26_949+27dupCC

Variant names:

• chr19-45363958-T-TGG
• rs766117419
• NM_000400.4:c.949+26_949+27dupCC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000400.4(ERCC2):​c.949+26_949+27dupCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,531,948 control chromosomes in the GnomAD database, including 6 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0850
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00165 (251/151980) while in subpopulation NFE AF = 0.00237 (161/67868). AF 95% confidence interval is 0.00207. There are 1 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.949+26_949+27dupCC		intron	N/A	NP_000391.1
	ERCC2	NM_001440355.1		c.877+26_877+27dupCC		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.871+26_871+27dupCC		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.949+27_949+28insCC		intron	N/A	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.949+27_949+28insCC		intron	N/A	ENSP00000375808.4
	ERCC2	ENST00000391941.6	TSL:1	c.877+27_877+28insCC		intron	N/A	ENSP00000375805.2

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 151862 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00133

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00150 AC: 202 AN: 135026 AF XY: 0.00149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00205

Gnomad NFE exome AF: 0.00275

Gnomad OTH exome AF: 0.000733

GnomAD4 exome AF: 0.00276 AC: 3805 AN: 1379968 Hom.: 5 Cov.: 36 AF XY: 0.00265 AC XY: 1807 AN XY: 681394

African (AFR) AF: 0.000634 AC: 20 AN: 31526

American (AMR) AF: 0.00143 AC: 51 AN: 35746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25096

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35718

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79300

European-Finnish (FIN) AF: 0.00127 AC: 45 AN: 35346

Middle Eastern (MID) AF: 0.00110 AC: 6 AN: 5446

European-Non Finnish (NFE) AF: 0.00328 AC: 3526 AN: 1074134

Other (OTH) AF: 0.00267 AC: 154 AN: 57656

GnomAD4 genome AF: 0.00165 AC: 251 AN: 151980 Hom.: 1 Cov.: 0 AF XY: 0.00182 AC XY: 135 AN XY: 74290

African (AFR) AF: 0.00106 AC: 44 AN: 41498

American (AMR) AF: 0.00190 AC: 29 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00133 AC: 14 AN: 10560

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

European-Non Finnish (NFE) AF: 0.00237 AC: 161 AN: 67868

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.000796 Hom.: 408

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.085
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs766117419; hg19: chr19-45867216;