Genetic Variant NM_000122.2:c.1946-1624C>T (chr2-127262970-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000122.2(ERCC3):c.1946-1624C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,084 control chromosomes in the GnomAD database, including 2,967 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 2967 hom., cov: 32)

Exomes 𝑓: 0.063 ( 0 hom. )

Consequence

ERCC3
NM_000122.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.689

Publications

21 publications found

Variant links:

Genes affected

ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ERCC3 Gene-Disease associations (from GenCC):

trichothiodystrophy 2, photosensitive
Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
xeroderma pigmentosum group B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
trichothiodystrophy 1, photosensitive
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
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
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ERCC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.01).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000122.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERCC3	NM_000122.2	MANE Select	c.1946-1624C>T	intron	N/A	NP_000113.1	P19447
ERCC3	NM_001303416.2		c.1754-1624C>T	intron	N/A	NP_001290345.1
ERCC3	NM_001303418.2		c.1754-1624C>T	intron	N/A	NP_001290347.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERCC3	ENST00000285398.7	TSL:1 MANE Select	c.1946-1624C>T	intron	N/A	ENSP00000285398.2	P19447
ERCC3	ENST00000647169.1		c.2021-1624C>T	intron	N/A	ENSP00000495619.1	A0A2R8Y6W8
ERCC3	ENST00000918332.1		c.1997-1624C>T	intron	N/A	ENSP00000588391.1

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27649

AN:

151950

Hom.:

2960

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0704

Gnomad AMI

AF:

0.0824

Gnomad AMR

AF:

0.168

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.264

Gnomad SAS

AF:

0.337

Gnomad FIN

AF:

0.272

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.224

Gnomad OTH

AF:

0.191

GnomAD4 exome

AF:

0.0625

AC:

AN:

Hom.:

AF XY:

0.0833

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.182

AC:

27661

AN:

152068

Hom.:

2967

Cov.:

AF XY:

0.186

AC XY:

13852

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0703

AC:

2917

AN:

41506

American (AMR)

AF:

0.168

AC:

2570

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

525

AN:

3472

East Asian (EAS)

AF:

0.264

AC:

1364

AN:

5170

South Asian (SAS)

AF:

0.337

AC:

1622

AN:

4812

European-Finnish (FIN)

AF:

0.272

AC:

2871

AN:

10540

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.224

AC:

15251

AN:

67974

Other (OTH)

AF:

0.198

AC:

419

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1126

2251

3377

4502

5628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

314

628

942

1256

1570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.180

Hom.:

463

Bravo

AF:

0.166

Asia WGS

AF:

0.308

AC:

1070

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.64

(source)

DANN

Benign

0.12

PhyloP100

-0.69

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over