9-95876046-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020207.7(ERCC6L2):c.8C>A(p.Pro3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 1,588,756 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (72 hom.)
• Consequence: ERCC6L2 NM_020207.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.09

Genes affected

ERCC6L2 (HGNC:26922): (ERCC excision repair 6 like 2) This gene encodes a member of the Snf2 family of helicase-like proteins. The encoded protein may play a role in DNA repair and mitochondrial function. Mutations in this gene have been associated with bone marrow failure syndrome 2. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Apr 2014]

ERCC6L2-AS1 (HGNC:27858): (ERCC6L2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025633276).
• BP6: Variant 9-95876046-C-A is Benign according to our data. Variant chr9-95876046-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1166945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00614 (935/152346) while in subpopulation NFE AF= 0.00947 (644/68022). AF 95% confidence interval is 0.00886. There are 6 homozygotes in gnomad4. There are 454 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6L2	NM_020207.7	c.8C>A	p.Pro3Gln	missense_variant	1/19	ENST00000653738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6L2	ENST00000653738.2	c.8C>A	p.Pro3Gln	missense_variant	1/19		NM_020207.7	P2

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 935 AN: 152228 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00947

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00618 AC: 1261 AN: 203882 Hom.: 8 AF XY: 0.00581 AC XY: 645 AN XY: 110928

Gnomad AFR exome AF: 0.00165

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00354

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.00938

Gnomad OTH exome AF: 0.00484

GnomAD4 exome AF: 0.00905 AC: 13006 AN: 1436410 Hom.: 72 Cov.: 32 AF XY: 0.00857 AC XY: 6106 AN XY: 712436

Gnomad4 AFR exome AF: 0.00110

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000643

Gnomad4 FIN exome AF: 0.0163

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.00697

GnomAD4 genome AF: 0.00614 AC: 935 AN: 152346 Hom.: 6 Cov.: 32 AF XY: 0.00609 AC XY: 454 AN XY: 74500

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.00947

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00735 Hom.: 8

Bravo AF: 0.00504

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00162 AC: 7

ESP6500EA AF: 0.00856 AC: 73

ExAC AF: 0.00565 AC: 677

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ERCC6L2: BP4, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 21, 2021

- -

ERCC6L2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	6.9
Dann	Benign	0.84
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.33
Sift	Benign	0.053	T
Sift4G	Benign	0.12	T
Vest4		0.11
MVP		0.25
MPC		0.20
ClinPred		0.0084	T
GERP RS		-3.1
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs151308487; hg19: chr9-98638328; COSMIC: COSV99998214; COSMIC: COSV99998214;