6-43046561-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014780.5(CUL7):c.2438A>G(p.Gln813Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,614,046 control chromosomes in the GnomAD database, including 762,334 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q813Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.98 ( 73002 hom., cov: 31)

Exomes 𝑓: 0.97 ( 689332 hom. )

Consequence

CUL7
NM_014780.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.49

Publications

23 publications found

Variant links:

Genes affected

CUL7 (HGNC:21024): (cullin 7) The protein encoded by this gene is a component of an E3 ubiquitin-protein ligase complex. The encoded protein interacts with TP53, CUL9, and FBXW8 proteins. Defects in this gene are a cause of 3M syndrome type 1 (3M1). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

CUL7 links:

KLC4 (HGNC:21624): (kinesin light chain 4) Predicted to be located in cytoplasm and microtubule. Predicted to be part of kinesin complex. [provided by Alliance of Genome Resources, Apr 2022]

KLC4 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=6.3990467E-7).

BP6

Variant 6-43046561-T-C is Benign according to our data. Variant chr6-43046561-T-C is described in ClinVar as Benign. ClinVar VariationId is 260436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL7	NM_014780.5 link	c.2438A>G	p.Gln813Arg	missense_variant	Exon 11 of 26	ENST00000265348.9	NP_055595.2	Q14999-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL7	ENST00000265348.9 link	c.2438A>G	p.Gln813Arg	missense_variant	Exon 11 of 26	1	NM_014780.5	ENSP00000265348.4		Q14999-1

Frequencies

GnomAD3 genomes

AF:

0.979

AC:

148924

AN:

152112

Hom.:

72939

Cov.:

show subpopulations

Gnomad AFR

AF:

0.994

Gnomad AMI

AF:

0.993

Gnomad AMR

AF:

0.982

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.988

Gnomad FIN

AF:

0.995

Gnomad MID

AF:

0.949

Gnomad NFE

AF:

0.969

Gnomad OTH

AF:

0.973

GnomAD2 exomes

AF:

0.976

AC:

245330

AN:

251312

AF XY:

0.975

show subpopulations

Gnomad AFR exome

AF:

0.995

Gnomad AMR exome

AF:

0.985

Gnomad ASJ exome

AF:

0.894

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.992

Gnomad NFE exome

AF:

0.968

Gnomad OTH exome

AF:

0.971

GnomAD4 exome

AF:

0.971

AC:

1419455

AN:

1461816

Hom.:

689332

Cov.:

120

AF XY:

0.971

AC XY:

706131

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.995

AC:

33322

AN:

33480

American (AMR)

AF:

0.983

AC:

43958

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.891

AC:

23284

AN:

26132

East Asian (EAS)

AF:

0.999

AC:

39675

AN:

39700

South Asian (SAS)

AF:

0.989

AC:

85348

AN:

86258

European-Finnish (FIN)

AF:

0.992

AC:

52966

AN:

53420

Middle Eastern (MID)

AF:

0.933

AC:

5384

AN:

5768

European-Non Finnish (NFE)

AF:

0.969

AC:

1076940

AN:

1111952

Other (OTH)

AF:

0.970

AC:

58578

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

2880

5759

8639

11518

14398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21650

43300

64950

86600

108250

<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:

0.979

AC:

149046

AN:

152230

Hom.:

73002

Cov.:

AF XY:

0.981

AC XY:

73033

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.994

AC:

41258

AN:

41514

American (AMR)

AF:

0.982

AC:

15012

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

3106

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5172

AN:

5174

South Asian (SAS)

AF:

0.988

AC:

4775

AN:

4832

European-Finnish (FIN)

AF:

0.995

AC:

10578

AN:

10628

Middle Eastern (MID)

AF:

0.949

AC:

277

AN:

292

European-Non Finnish (NFE)

AF:

0.969

AC:

65910

AN:

68006

Other (OTH)

AF:

0.973

AC:

2052

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

164

328

491

655

819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.969

Hom.:

45115

Bravo

AF:

0.978

TwinsUK

AF:

0.972

AC:

3603

ALSPAC

AF:

0.969

AC:

3735

ESP6500AA

AF:

0.995

AC:

4382

ESP6500EA

AF:

0.968

AC:

8323

ExAC

AF:

0.976

AC:

118544

Asia WGS

AF:

0.992

AC:

3449

AN:

3478

EpiCase

AF:

0.969

EpiControl

AF:

0.964

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

3M syndrome 1

Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.24

T;T

MetaRNN

Benign

6.4e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.46

N;.

PhyloP100

1.5

PrimateAI

Benign

0.35

PROVEAN

Benign

0.31

N;N

REVEL

Benign

0.087

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.088

MPC

0.21

ClinPred

0.000019

GERP RS

1.6

Varity_R

0.022

gMVP

0.19

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over