chr2-209993421-C-T

Variant names:

• chr2-209993421-C-T
• rs61271372
• NM_001371986.1:c.9503C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001371986.1(UNC80):​c.9503C>T​(p.Pro3168Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00231 in 1,551,362 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3168A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (25 hom.)
• Consequence: UNC80 NM_001371986.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.29
• Publications: 4 publications found

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]

UNC80 Gene-Disease associations (from GenCC):

• hypotonia, infantile, with psychomotor retardation and characteristic facies 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, ClinGen
• hypotonia, infantile, with psychomotor retardation and characteristic facies

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032159388).
• BP6: Variant 2-209993421-C-T is Benign according to our data. Variant chr2-209993421-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0108 (1651/152276) while in subpopulation AFR AF = 0.0349 (1451/41532). AF 95% confidence interval is 0.0334. There are 23 homozygotes in GnomAd4. There are 777 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371986.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	NM_001371986.1	MANE Select	c.9503C>T	p.Pro3168Leu	missense	Exon 63 of 65	NP_001358915.1
	UNC80	NM_032504.2		c.9305C>T	p.Pro3102Leu	missense	Exon 62 of 64	NP_115893.1
	UNC80	NM_182587.4		c.9233C>T	p.Pro3078Leu	missense	Exon 61 of 63	NP_872393.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	ENST00000673920.1	MANE Select	c.9503C>T	p.Pro3168Leu	missense	Exon 63 of 65	ENSP00000501211.1
	UNC80	ENST00000439458.5	TSL:5	c.9305C>T	p.Pro3102Leu	missense	Exon 62 of 64	ENSP00000391088.1
	UNC80	ENST00000673951.2		c.9299C>T	p.Pro3100Leu	missense	Exon 62 of 64	ENSP00000501012.1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1645 AN: 152158 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00273 AC: 428 AN: 156506 AF XY: 0.00211

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.00329

Gnomad ASJ exome AF: 0.00176

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000594

Gnomad NFE exome AF: 0.000611

Gnomad OTH exome AF: 0.00250

GnomAD4 exome AF: 0.00138 AC: 1926 AN: 1399086 Hom.: 25 Cov.: 30 AF XY: 0.00121 AC XY: 834 AN XY: 690054

African (AFR) AF: 0.0364 AC: 1151 AN: 31584

American (AMR) AF: 0.00426 AC: 152 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 59 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.000164 AC: 13 AN: 79192

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49258

Middle Eastern (MID) AF: 0.00544 AC: 31 AN: 5696

European-Non Finnish (NFE) AF: 0.000271 AC: 292 AN: 1078768

Other (OTH) AF: 0.00391 AC: 227 AN: 57994

GnomAD4 genome AF: 0.0108 AC: 1651 AN: 152276 Hom.: 23 Cov.: 32 AF XY: 0.0104 AC XY: 777 AN XY: 74472

African (AFR) AF: 0.0349 AC: 1451 AN: 41532

American (AMR) AF: 0.00830 AC: 127 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68030

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00394 Hom.: 34

Bravo AF: 0.0128

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0260 AC: 36

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.00402 AC: 103

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

UNC80-related disorder Benign:1

Apr 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.82	P
Vest4		0.46
MVP		0.41
MPC		1.1
ClinPred		0.027	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.31
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61271372; hg19: chr2-210858145;