chr19-45351413-C-T

Variant names:

• chr19-45351413-C-T
• rs534559459
• NM_000400.4:c.*216G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000400.4(ERCC2):​c.*216G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,597,522 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: ERCC2 NM_000400.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.867
• Publications: 0 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]

KLC3 (HGNC:20717): (kinesin light chain 3) This gene encodes a member of the kinesin light chain gene family. Kinesins are molecular motors involved in the transport of cargo along microtubules, and are composed of two kinesin heavy chain (KHC) and two kinesin light chain (KLC) molecules. KLCs are thought to typically be involved in binding cargo and regulating kinesin activity. In the rat, a protein similar to this gene product is expressed in post-meiotic spermatids, where it associates with structural components of sperm tails and mitochondria. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-45351413-C-T is Benign according to our data. Variant chr19-45351413-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 892628.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00181 (275/152306) while in subpopulation AFR AF = 0.00524 (218/41568). AF 95% confidence interval is 0.00467. There are 1 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.*216G>A		3_prime_UTR	Exon 23 of 23	NP_000391.1
	KLC3	NM_177417.3	MANE Select	c.*56C>T		3_prime_UTR	Exon 13 of 13	NP_803136.2
	ERCC2	NM_001440355.1		c.*216G>A		3_prime_UTR	Exon 23 of 23	NP_001427284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.*216G>A		3_prime_UTR	Exon 23 of 23	ENSP00000375809.4
	KLC3	ENST00000391946.7	TSL:1 MANE Select	c.*56C>T		3_prime_UTR	Exon 13 of 13	ENSP00000375810.2
	KLC3	ENST00000470402.1	TSL:1	c.*56C>T		3_prime_UTR	Exon 12 of 12	ENSP00000436019.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000365 AC: 527 AN: 1445216 Hom.: 1 Cov.: 37 AF XY: 0.000366 AC XY: 263 AN XY: 718214

African (AFR) AF: 0.00579 AC: 193 AN: 33324

American (AMR) AF: 0.000834 AC: 37 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.00351 AC: 91 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43326

Middle Eastern (MID) AF: 0.000698 AC: 4 AN: 5728

European-Non Finnish (NFE) AF: 0.000134 AC: 148 AN: 1107210

Other (OTH) AF: 0.000885 AC: 53 AN: 59890

GnomAD4 genome AF: 0.00181 AC: 275 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74492

African (AFR) AF: 0.00524 AC: 218 AN: 41568

American (AMR) AF: 0.00190 AC: 29 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.00194

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Xeroderma pigmentosum, group D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.46
DANN	Benign	0.74
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism

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: rs534559459; hg19: chr19-45854671;