Variant chr6-41033905-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_173561.3(UNC5CL):c.662G>C(p.Cys221Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00143 in 1,613,662 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

UNC5CL
NM_173561.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.86

Variant links:

Genes affected

UNC5CL (HGNC:21203): (unc-5 family C-terminal like) Enables peptidase activity. Acts upstream of or within positive regulation of I-kappaB kinase/NF-kappaB signaling and positive regulation of JNK cascade. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

UNC5CL links:

OARD1 (HGNC:21257): (O-acyl-ADP-ribose deacylase 1) The protein encoded by this gene is a deacylase that can convert O-acetyl-ADP-ribose to ADP-ribose and acetate, O-propionyl-ADP-ribose to ADP-ribose and propionate, and O-butyryl-ADP-ribose to ADP-ribose and butyrate. The ADP-ribose product is able to inhibit these reactions through a competitive feedback loop. [provided by RefSeq, Jul 2016]

OARD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.35303038).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC5CL	NM_173561.3 linkuse as main transcript	c.662G>C	p.Cys221Ser	missense_variant	3/9	ENST00000244565.8	NP_775832.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
UNC5CL	ENST00000244565.8 linkuse as main transcript	c.662G>C	p.Cys221Ser	missense_variant	3/9	1	NM_173561.3	ENSP00000244565	P1
UNC5CL	ENST00000373164.1 linkuse as main transcript	c.662G>C	p.Cys221Ser	missense_variant	2/8	1		ENSP00000362258	P1
OARD1	ENST00000482853.5 linkuse as main transcript	c.*735G>C		3_prime_UTR_variant, NMD_transcript_variant	5/5	2		ENSP00000420472

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

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:

0.00144

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000742

AC:

185

AN:

249278

Hom.:

AF XY:

0.000703

AC XY:

AN XY:

135068

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00149

AC:

2182

AN:

1461360

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1046

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000515

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.00185

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.000840

AC:

128

AN:

152302

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.000854

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000700

AC:

EpiCase

AF:

0.00142

EpiControl

AF:

0.00166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2021

The c.662G>C (p.C221S) alteration is located in exon 3 (coding exon 2) of the UNC5CL gene. This alteration results from a G to C substitution at nucleotide position 662, causing the cysteine (C) at amino acid position 221 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.65

T;.

M_CAP

Benign

0.013

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.84

MutPred

0.67

Gain of disorder (P = 7e-04);Gain of disorder (P = 7e-04);

MVP

0.63

MPC

0.46

ClinPred

0.10

GERP RS

3.9

Varity_R

0.82

gMVP

0.72

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over