2-209772130-C-T

Variant names:

• chr2-209772130-C-T
• rs145528914
• NM_001371986.1:c.58C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001371986.1(UNC80):​c.58C>T​(p.Leu20Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,548,676 control chromosomes in the GnomAD database, including 551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (29 hom., cov: 31)
  • Exomes 𝑓: 0.024 (522 hom.)
• Consequence: UNC80 NM_001371986.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.35
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), Illumina
• hypotonia, infantile, with psychomotor retardation and characteristic facies

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-209772130-C-T is Benign according to our data. Variant chr2-209772130-C-T is described in ClinVar as Benign. ClinVar VariationId is 1670291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0163 (2473/151980) while in subpopulation NFE AF = 0.0255 (1733/67918). AF 95% confidence interval is 0.0245. There are 29 homozygotes in GnomAd4. There are 1117 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	NM_001371986.1	MANE Select	c.58C>T	p.Leu20Leu	synonymous	Exon 1 of 65	NP_001358915.1	A0A669KBC5
	UNC80	NM_032504.2		c.58C>T	p.Leu20Leu	synonymous	Exon 1 of 64	NP_115893.1	Q8N2C7-1
	UNC80	NM_182587.4		c.58C>T	p.Leu20Leu	synonymous	Exon 1 of 63	NP_872393.3	Q8N2C7-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	ENST00000673920.1	MANE Select	c.58C>T	p.Leu20Leu	synonymous	Exon 1 of 65	ENSP00000501211.1	A0A669KBC5
	UNC80	ENST00000478701.1	TSL:1	n.138C>T		non_coding_transcript_exon	Exon 1 of 8
	UNC80	ENST00000439458.5	TSL:5	c.58C>T	p.Leu20Leu	synonymous	Exon 1 of 64	ENSP00000391088.1	Q8N2C7-1

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2472 AN: 151874 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.00442

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0156 AC: 2353 AN: 150462 AF XY: 0.0157

Gnomad AFR exome AF: 0.00453

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.0000915

Gnomad FIN exome AF: 0.00164

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0244 AC: 34109 AN: 1396696 Hom.: 522 Cov.: 31 AF XY: 0.0239 AC XY: 16470 AN XY: 688946

African (AFR) AF: 0.00369 AC: 116 AN: 31402

American (AMR) AF: 0.0203 AC: 723 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 413 AN: 25128

East Asian (EAS) AF: 0.0000561 AC: 2 AN: 35646

South Asian (SAS) AF: 0.00301 AC: 238 AN: 79158

European-Finnish (FIN) AF: 0.00224 AC: 109 AN: 48678

Middle Eastern (MID) AF: 0.0108 AC: 54 AN: 5008

European-Non Finnish (NFE) AF: 0.0287 AC: 30979 AN: 1078166

Other (OTH) AF: 0.0255 AC: 1475 AN: 57842

GnomAD4 genome AF: 0.0163 AC: 2473 AN: 151980 Hom.: 29 Cov.: 31 AF XY: 0.0150 AC XY: 1117 AN XY: 74266

African (AFR) AF: 0.00441 AC: 183 AN: 41506

American (AMR) AF: 0.0249 AC: 381 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00274 AC: 29 AN: 10570

Middle Eastern (MID) AF: 0.0138 AC: 4 AN: 290

European-Non Finnish (NFE) AF: 0.0255 AC: 1733 AN: 67918

Other (OTH) AF: 0.0143 AC: 30 AN: 2100

Alfa AF: 0.0219 Hom.: 15

Bravo AF: 0.0192

Asia WGS AF: 0.00232 AC: 8 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.3
DANN	Benign	0.93
PhyloP100		2.3
PromoterAI		0.0085	Neutral
Mutation Taster		=100/0	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

dbSNP: rs145528914; hg19: chr2-210636854;