chr19-45361933-CTTTT-C

Variant names:

• chr19-45361933-CTTTT-C
• rs3916823
• NM_000400.4:c.1119-295_1119-292delAAAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000400.4(ERCC2):​c.1119-295_1119-292delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 400,922 control chromosomes in the GnomAD database, including 3,405 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1109 hom., cov: 30)
  • Exomes 𝑓: 0.13 (2296 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.818
• Publications: 2 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 -10 ACMG points.

• BP6: Variant 19-45361933-CTTTT-C is Benign according to our data. Variant chr19-45361933-CTTTT-C is described in ClinVar as Benign. ClinVar VariationId is 1232033.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 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.1119-295_1119-292delAAAA		intron	N/A	NP_000391.1
	ERCC2	NM_001440355.1		c.1047-295_1047-292delAAAA		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.1041-295_1041-292delAAAA		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.1119-295_1119-292delAAAA		intron	N/A	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.1119-295_1119-292delAAAA		intron	N/A	ENSP00000375808.4
	ERCC2	ENST00000391941.6	TSL:1	c.1047-295_1047-292delAAAA		intron	N/A	ENSP00000375805.2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16116 AN: 151910 Hom.: 1105 Cov.: 30

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.127 AC: 31617 AN: 248896 Hom.: 2296 AF XY: 0.128 AC XY: 16926 AN XY: 132534

African (AFR) AF: 0.0221 AC: 168 AN: 7618

American (AMR) AF: 0.102 AC: 1173 AN: 11520

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 1088 AN: 7352

East Asian (EAS) AF: 0.0976 AC: 1459 AN: 14954

South Asian (SAS) AF: 0.131 AC: 4997 AN: 38020

European-Finnish (FIN) AF: 0.107 AC: 1174 AN: 11014

Middle Eastern (MID) AF: 0.131 AC: 331 AN: 2534

European-Non Finnish (NFE) AF: 0.137 AC: 19527 AN: 142104

Other (OTH) AF: 0.123 AC: 1700 AN: 13780

GnomAD4 genome AF: 0.106 AC: 16131 AN: 152026 Hom.: 1109 Cov.: 30 AF XY: 0.105 AC XY: 7824 AN XY: 74306

African (AFR) AF: 0.0260 AC: 1079 AN: 41504

American (AMR) AF: 0.112 AC: 1706 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3468

East Asian (EAS) AF: 0.111 AC: 572 AN: 5160

South Asian (SAS) AF: 0.129 AC: 620 AN: 4814

European-Finnish (FIN) AF: 0.120 AC: 1263 AN: 10566

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9995 AN: 67948

Other (OTH) AF: 0.114 AC: 241 AN: 2108

Alfa AF: 0.0493 Hom.: 41

Bravo AF: 0.104

Asia WGS AF: 0.127 AC: 439 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.82
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: rs3916823; hg19: chr19-45865191;