chr8-12137874-T-A

Variant names:

• chr8-12137874-T-A
• rs201233406
• NM_201402.3:c.887A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_201402.3(USP17L2):​c.887A>T​(p.Gln296Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,526,540 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (278 hom.)
• Consequence: USP17L2 NM_201402.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.688
• Publications: 2 publications found

Genes affected

USP17L2 (HGNC:34434): (ubiquitin specific peptidase 17 like family member 2) DUB3 is a member of the ubiquitin processing protease (UBP) subfamily of deubiquitinating enzymes. See USP1 (MIM 603478) for background information.[supplied by OMIM, Mar 2008]

FAM66D (HGNC:24159): (family with sequence similarity 66 member D)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.018048763).
• BP6: Variant 8-12137874-T-A is Benign according to our data. Variant chr8-12137874-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2658425.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201402.3. 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
	USP17L2	NM_201402.3	MANE Select	c.887A>T	p.Gln296Leu	missense	Exon 1 of 1	NP_958804.2	Q6R6M4
	FAM66D	NR_027425.1		n.609-7549T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP17L2	ENST00000333796.4	TSL:6 MANE Select	c.887A>T	p.Gln296Leu	missense	Exon 1 of 1	ENSP00000333329.3	Q6R6M4
	FAM66D	ENST00000434078.3	TSL:5	n.545-7765T>A		intron	N/A
	FAM66D	ENST00000653269.1		n.706-7549T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 245 AN: 140908 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.000561

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000648

Gnomad ASJ AF: 0.00329

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000203

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00305

Gnomad OTH AF: 0.00205

GnomAD2 exomes AF: 0.00151 AC: 334 AN: 221844 AF XY: 0.00151

Gnomad AFR exome AF: 0.000243

Gnomad AMR exome AF: 0.000727

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000100

Gnomad NFE exome AF: 0.00267

Gnomad OTH exome AF: 0.000892

GnomAD4 exome AF: 0.00195 AC: 2706 AN: 1385538 Hom.: 278 Cov.: 39 AF XY: 0.00188 AC XY: 1296 AN XY: 689462

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

African (AFR) AF: 0.000254 AC: 8 AN: 31466

American (AMR) AF: 0.000543 AC: 23 AN: 42324

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 93 AN: 25096

East Asian (EAS) AF: 0.0000288 AC: 1 AN: 34764

South Asian (SAS) AF: 0.00 AC: 0 AN: 78236

European-Finnish (FIN) AF: 0.000119 AC: 6 AN: 50632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4018

European-Non Finnish (NFE) AF: 0.00234 AC: 2481 AN: 1062026

Other (OTH) AF: 0.00165 AC: 94 AN: 56976

⚠️ 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.

GnomAD4 genome AF: 0.00174 AC: 245 AN: 141002 Hom.: 31 Cov.: 33 AF XY: 0.00162 AC XY: 111 AN XY: 68460

African (AFR) AF: 0.000560 AC: 21 AN: 37516

American (AMR) AF: 0.000647 AC: 9 AN: 13902

Ashkenazi Jewish (ASJ) AF: 0.00329 AC: 11 AN: 3340

East Asian (EAS) AF: 0.00 AC: 0 AN: 4338

South Asian (SAS) AF: 0.00 AC: 0 AN: 4050

European-Finnish (FIN) AF: 0.000203 AC: 2 AN: 9850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.00305 AC: 198 AN: 64940

Other (OTH) AF: 0.00203 AC: 4 AN: 1970

Alfa AF: 0.00277 Hom.: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00208 AC: 12

ExAC AF: 0.00162 AC: 180

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.4
DANN	Benign	0.86
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.69
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.035
Sift	Benign	0.047	D
Sift4G	Benign	0.12	T
Polyphen		0.47	P
Vest4		0.15
MVP		0.20
MPC		0.96
ClinPred		0.092	T
GERP RS		-1.5
Varity_R		0.11
gMVP		0.034
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: rs201233406; hg19: chr8-11995383; COSMIC: COSV61555851; COSMIC: COSV61555851;