chr2-209772171-G-A

Variant names:

• chr2-209772171-G-A
• rs200211384
• NM_001371986.1:c.92+7G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001371986.1(UNC80):​c.92+7G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00676 in 1,536,440 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (54 hom.)
• Consequence: UNC80 NM_001371986.1 splice_region, intron
• Scores: Splicing: ADA: 0.002059
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.98

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

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 2-209772171-G-A is Benign according to our data. Variant chr2-209772171-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 710314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-209772171-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00446 (676/151434) while in subpopulation NFE AF = 0.00777 (526/67702). AF 95% confidence interval is 0.00722. There are 4 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC80	NM_001371986.1	c.92+7G>A		splice_region_variant, intron_variant	Intron 1 of 64	ENST00000673920.1	NP_001358915.1
UNC80	NM_032504.2	c.92+7G>A		splice_region_variant, intron_variant	Intron 1 of 63		NP_115893.1
UNC80	NM_182587.4	c.92+7G>A		splice_region_variant, intron_variant	Intron 1 of 62		NP_872393.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC80	ENST00000673920.1	c.92+7G>A		splice_region_variant, intron_variant	Intron 1 of 64		NM_001371986.1	ENSP00000501211.1

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 674 AN: 151326 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00309

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.00355

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00777

Gnomad OTH AF: 0.00338

GnomAD2 exomes AF: 0.00397 AC: 528 AN: 133046 AF XY: 0.00403

Gnomad AFR exome AF: 0.000971

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.000255

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.00813

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00701 AC: 9714 AN: 1385006 Hom.: 54 Cov.: 31 AF XY: 0.00681 AC XY: 4655 AN XY: 683158

Gnomad4 AFR exome AF: 0.000962 AC: 29 AN: 30148

Gnomad4 AMR exome AF: 0.00153 AC: 54 AN: 35240

Gnomad4 ASJ exome AF: 0.000648 AC: 16 AN: 24702

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 34382

Gnomad4 SAS exome AF: 0.00172 AC: 135 AN: 78692

Gnomad4 FIN exome AF: 0.00430 AC: 206 AN: 47854

Gnomad4 NFE exome AF: 0.00829 AC: 8890 AN: 1072560

Gnomad4 Remaining exome AF: 0.00662 AC: 379 AN: 57220

GnomAD4 genome AF: 0.00446 AC: 676 AN: 151434 Hom.: 4 Cov.: 32 AF XY: 0.00406 AC XY: 300 AN XY: 73950

Gnomad4 AFR AF: 0.00113 AC: 0.00113477 AN: 0.00113477

Gnomad4 AMR AF: 0.00309 AC: 0.00309007 AN: 0.00309007

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00249 AC: 0.00249273 AN: 0.00249273

Gnomad4 FIN AF: 0.00355 AC: 0.00354678 AN: 0.00354678

Gnomad4 NFE AF: 0.00777 AC: 0.00776934 AN: 0.00776934

Gnomad4 OTH AF: 0.00334 AC: 0.00333969 AN: 0.00333969

Alfa AF: 0.00552 Hom.: 1

Bravo AF: 0.00447

Asia WGS AF: 0.000580 AC: 2 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Nov 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

UNC80: BP4, BS2 -

UNC80-related disorder Benign:1

Mar 25, 2020

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.96
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
dbscSNV1_RF	Benign	0.054
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: rs200211384; hg19: chr2-210636895;