rs869025317

Variant names:

• chr2-209959707-G-C
• rs869025317
• NM_001371986.1:c.7805G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001371986.1(UNC80):​c.7805G>C​(p.Arg2602Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UNC80 NM_001371986.1 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.88

Genes affected

UNC80 (HGNC:26582): (unc-80 homolog, NALCN channel complex subunit) The protein encoded by this gene is a component of a voltage-independent 'leak' ion-channel complex, in which it performs essential functions, such as serving as a bridge between two other components (sodium leak channel non-selective and UNC79) and as a scaffold for Src kinases. Leak channels play an importnat role in establishment and maintenance of resting membrane potentials in neurons. Mutations in this gene are associated with congenital infantile encephalopathy, intellectual disability and growth issues. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-209959707-G-C is Pathogenic according to our data. Variant chr2-209959707-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222011.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-209959707-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC80	NM_001371986.1	c.7805G>C	p.Arg2602Thr	missense_variant, splice_region_variant	Exon 51 of 65	ENST00000673920.1	NP_001358915.1
UNC80	NM_032504.2	c.7607G>C	p.Arg2536Thr	missense_variant, splice_region_variant	Exon 50 of 64		NP_115893.1
UNC80	NM_182587.4	c.7592G>C	p.Arg2531Thr	missense_variant, splice_region_variant	Exon 50 of 63		NP_872393.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC80	ENST00000673920.1	c.7805G>C	p.Arg2602Thr	missense_variant, splice_region_variant	Exon 51 of 65		NM_001371986.1	ENSP00000501211.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 Pathogenic:2

Jan 07, 2016

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 11, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.90
MutPred		0.50		Loss of helix (P = 0.028);.;.;
MVP		0.59
MPC		1.3
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.74
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869025317; hg19: chr2-210824431; COSMIC: COSV99780515; COSMIC: COSV99780515;