Genetic Variant UNC119:p.Gly22Val (chr17-28552493-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005148.4(UNC119):c.65G>T(p.Gly22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,570,244 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 12 hom., cov: 31)

Exomes 𝑓: 0.00062 ( 5 hom. )

Consequence

UNC119
NM_005148.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:5

Conservation

PhyloP100: 2.53

Publications

8 publications found

Variant links:

Genes affected

UNC119 (HGNC:12565): (unc-119 lipid binding chaperone) This gene is specifically expressed in the photoreceptors in the retina. The encoded product shares strong homology with the C. elegans unc119 protein and it can functionally complement the C. elegans unc119 mutation. It has been localized to the photoreceptor synapses in the outer plexiform layer of the retina, and suggested to play a role in the mechanism of photoreceptor neurotransmitter release through the synaptic vesicle cycle. Two transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

UNC119 links:

RSKR (HGNC:26314): (ribosomal protein S6 kinase related) Predicted to enable protein kinase activity. Predicted to be involved in protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

RSKR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.003015697).

BP6

Variant 17-28552493-C-A is Benign according to our data. Variant chr17-28552493-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 88737.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 = 0.00638 (971/152248) while in subpopulation AFR AF = 0.022 (916/41572). AF 95% confidence interval is 0.0208. There are 12 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 971 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005148.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UNC119	NM_005148.4	MANE Select	c.65G>T	p.Gly22Val	missense	Exon 1 of 5	NP_005139.1	Q13432-1
UNC119	NM_054035.2		c.65G>T	p.Gly22Val	missense	Exon 1 of 4	NP_473376.1	Q13432-2
UNC119	NM_001330166.2		c.-249G>T		5_prime_UTR	Exon 1 of 6	NP_001317095.1	K7EN86

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UNC119	ENST00000335765.9	TSL:1 MANE Select	c.65G>T	p.Gly22Val	missense	Exon 1 of 5	ENSP00000337040.3	Q13432-1
UNC119	ENST00000301032.8	TSL:1	c.65G>T	p.Gly22Val	missense	Exon 1 of 4	ENSP00000301032.4	Q13432-2
RSKR	ENST00000481916.6	TSL:1	n.*1195+51558G>T		intron	N/A	ENSP00000436369.2	Q96LW2-2

Frequencies

GnomAD3 genomes

AF:

0.00632

AC:

962

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00160

AC:

290

AN:

181372

AF XY:

0.00132

show subpopulations

Gnomad AFR exome

AF:

0.0286

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00217

GnomAD4 exome

AF:

0.000618

AC:

877

AN:

1417996

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

393

AN XY:

704522

show subpopulations

African (AFR)

AF:

0.0204

AC:

619

AN:

30364

American (AMR)

AF:

0.00169

AC:

AN:

42126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25062

East Asian (EAS)

AF:

0.00

AC:

AN:

36466

South Asian (SAS)

AF:

0.0000968

AC:

AN:

82620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37180

Middle Eastern (MID)

AF:

0.00112

AC:

AN:

5358

European-Non Finnish (NFE)

AF:

0.0000855

AC:

AN:

1099838

Other (OTH)

AF:

0.00134

AC:

AN:

58982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

111

166

222

277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00638

AC:

971

AN:

152248

Hom.:

Cov.:

AF XY:

0.00648

AC XY:

482

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0220

AC:

916

AN:

41572

American (AMR)

AF:

0.00268

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67974

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00242

Hom.:

Bravo

AF:

0.00722

ESP6500AA

AF:

0.0142

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00173

AC:

197

Asia WGS

AF:

0.00116

AC:

AN:

3462

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Idiopathic CD4 lymphocytopenia (2)

not specified (2)

Cone-rod dystrophy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.1

PhyloP100

2.5

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.98

REVEL

Benign

0.14

Sift

Uncertain

0.021

Sift4G

Uncertain

0.048

Polyphen

0.13

Vest4

0.17

MVP

0.57

MPC

0.61

ClinPred

0.017

GERP RS

2.7

PromoterAI

-0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

gMVP

0.72

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over