Genetic Variant ERCC6L2:c.-32T>A (chr9-95876007-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020207.7(ERCC6L2):c.-32T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,421,120 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ERCC6L2
NM_020207.7 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.603

Publications

3 publications found

Variant links:

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 links:

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

ERCC6L2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020207.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERCC6L2	NM_020207.7	MANE Select	c.-32T>A	5_prime_UTR	Exon 1 of 19	NP_064592.3	Q5T890-1
ERCC6L2	NM_001375291.1		c.-32T>A	5_prime_UTR	Exon 1 of 19	NP_001362220.1
ERCC6L2	NM_001375292.1		c.-32T>A	5_prime_UTR	Exon 1 of 19	NP_001362221.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERCC6L2	ENST00000653738.2	MANE Select	c.-32T>A	5_prime_UTR	Exon 1 of 19	ENSP00000499221.2	Q5T890-1
ERCC6L2	ENST00000288985.13	TSL:1	c.-32T>A	5_prime_UTR	Exon 1 of 14	ENSP00000288985.8	A0A5F9UKL4
ERCC6L2-AS1	ENST00000321517.4	TSL:1	n.4A>T	non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1421120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703290

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32332

American (AMR)

AF:

0.00

AC:

AN:

39752

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25364

East Asian (EAS)

AF:

0.00

AC:

AN:

36930

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092590

Other (OTH)

AF:

0.00

AC:

AN:

58812

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.20

CADD

Benign

7.6

(source)

DANN

Benign

0.74

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0010

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.72

PhyloP100

-0.60

PROVEAN

Benign

1.3

REVEL

Benign

0.22

Sift

Benign

0.034

Sift4G

Pathogenic

0.0

Vest4

0.16

MutPred

0.93

Gain of methylation at M1 (P = 0.0206)

MVP

0.21

ClinPred

0.15

GERP RS

-6.5

PromoterAI

0.082

Neutral

(source)

gMVP

0.35

Mutation Taster

=187/13

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over