rs4253162

Variant names:

• chr10-49483314-T-C
• rs4253162
• NM_000124.4:c.1992+32A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-49483314-T-C
• chr10-49483314-T-A
• chr10-49483314-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000124.4(ERCC6):​c.1992+32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.903 in 1,607,482 control chromosomes in the GnomAD database, including 657,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (57451 hom., cov: 33)
  • Exomes 𝑓: 0.91 (600221 hom.)
• Consequence: ERCC6 NM_000124.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.836
• Publications: 19 publications found

Genes affected

ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

ERCC6 Gene-Disease associations (from GenCC):

• Cockayne spectrum with or without cerebrooculofacioskeletal syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Cockayne syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• UV-sensitive syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• UV-sensitive syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• premature ovarian failure 11

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-49483314-T-C is Benign according to our data. Variant chr10-49483314-T-C is described in ClinVar as Benign. ClinVar VariationId is 255163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000124.4. 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
	ERCC6	NM_000124.4	MANE Select	c.1992+32A>G		intron	N/A	NP_000115.1	Q03468-1
	ERCC6	NM_001346440.2		c.1992+32A>G		intron	N/A	NP_001333369.1	Q03468-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.1992+32A>G		intron	N/A	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000623073.3	TSL:1	n.6472+32A>G		intron	N/A
	ERCC6	ENST00000898255.1		c.1992+32A>G		intron	N/A	ENSP00000568314.1

Frequencies

GnomAD3 genomes AF: 0.865 AC: 131529 AN: 152138 Hom.: 57430 Cov.: 33

Gnomad AFR AF: 0.731

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.869

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.930

Gnomad MID AF: 0.904

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.887

GnomAD2 exomes AF: 0.913 AC: 229210 AN: 251038 AF XY: 0.917

Gnomad AFR exome AF: 0.731

Gnomad AMR exome AF: 0.947

Gnomad ASJ exome AF: 0.872

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.928

Gnomad NFE exome AF: 0.907

Gnomad OTH exome AF: 0.917

GnomAD4 exome AF: 0.908 AC: 1320691 AN: 1455224 Hom.: 600221 Cov.: 29 AF XY: 0.909 AC XY: 658259 AN XY: 724360

African (AFR) AF: 0.722 AC: 24078 AN: 33332

American (AMR) AF: 0.944 AC: 42184 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 22732 AN: 26074

East Asian (EAS) AF: 1.00 AC: 39632 AN: 39648

South Asian (SAS) AF: 0.946 AC: 81450 AN: 86128

European-Finnish (FIN) AF: 0.926 AC: 49374 AN: 53320

Middle Eastern (MID) AF: 0.897 AC: 5164 AN: 5756

European-Non Finnish (NFE) AF: 0.906 AC: 1002102 AN: 1106126

Other (OTH) AF: 0.897 AC: 53975 AN: 60142

GnomAD4 genome AF: 0.864 AC: 131598 AN: 152258 Hom.: 57451 Cov.: 33 AF XY: 0.870 AC XY: 64800 AN XY: 74482

African (AFR) AF: 0.730 AC: 30322 AN: 41514

American (AMR) AF: 0.924 AC: 14137 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.869 AC: 3015 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5181 AN: 5186

South Asian (SAS) AF: 0.955 AC: 4613 AN: 4830

European-Finnish (FIN) AF: 0.930 AC: 9873 AN: 10616

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.905 AC: 61547 AN: 68024

Other (OTH) AF: 0.888 AC: 1878 AN: 2114

Alfa AF: 0.879 Hom.: 20581

Bravo AF: 0.857

Asia WGS AF: 0.964 AC: 3351 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cerebrooculofacioskeletal syndrome 1 (1)
-	-	1	Cockayne syndrome type 2 (1)
-	-	1	DE SANCTIS-CACCHIONE SYNDROME (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	UV-sensitive syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.3
DANN	Benign	0.81
PhyloP100		-0.84
Mutation Taster		=18/82	disease causing

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: rs4253162; hg19: chr10-50691360;