2-209772141-G-C

Variant names:

• chr2-209772141-G-C
• rs906070422
• NM_001371986.1:c.69G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001371986.1(UNC80):​c.69G>C​(p.Gln23His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UNC80 NM_001371986.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC80	NM_001371986.1	c.69G>C	p.Gln23His	missense_variant	Exon 1 of 65	ENST00000673920.1	NP_001358915.1
UNC80	NM_032504.2	c.69G>C	p.Gln23His	missense_variant	Exon 1 of 64		NP_115893.1
UNC80	NM_182587.4	c.69G>C	p.Gln23His	missense_variant	Exon 1 of 63		NP_872393.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC80	ENST00000673920.1	c.69G>C	p.Gln23His	missense_variant	Exon 1 of 65		NM_001371986.1	ENSP00000501211.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.75
MutPred		0.54		Loss of MoRF binding (P = 0.0949);Loss of MoRF binding (P = 0.0949);
MVP		0.34
MPC		0.64
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.67
gMVP		0.92

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: rs906070422; hg19: chr2-210636865;