10-11462823-G-A

Variant names:

• chr10-11462823-G-A
• NM_014688.5:c.2105C>T

Variant summary

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

The NM_014688.5(USP6NL):​c.2105C>T​(p.Pro702Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP6NL NM_014688.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.16
• Publications: 0 publications found

Genes affected

USP6NL (HGNC:16858): (USP6 N-terminal like) Enables GTPase activator activity and small GTPase binding activity. Involved in several processes, including plasma membrane to endosome transport; positive regulation of GTPase activity; and retrograde transport, plasma membrane to Golgi. Located in cytoplasmic vesicle and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000301463 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP6NL	NM_014688.5	c.2105C>T	p.Pro702Leu	missense_variant	Exon 15 of 15	ENST00000609104.6	NP_055503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP6NL	ENST00000609104.6	c.2105C>T	p.Pro702Leu	missense_variant	Exon 15 of 15	1	NM_014688.5	ENSP00000476462.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2156C>T (p.P719L) alteration is located in exon 14 (coding exon 14) of the USP6NL gene. This alteration results from a C to T substitution at nucleotide position 2156, causing the proline (P) at amino acid position 719 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;.
PhyloP100		7.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.7	.;D;D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.56
MutPred		0.37		Loss of disorder (P = 0.0756);.;.;
MVP		0.80
MPC		0.58
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.24
gMVP		0.66
Mutation Taster		=81/19	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

hg19: chr10-11504822;