7-92245996-C-T

Variant names:

Variant summary

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

The NM_019004.2(ANKIB1):c.-614C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0896 in 234,902 control chromosomes in the GnomAD database, including 1,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.086 ( 779 hom., cov: 31)

Exomes 𝑓: 0.097 ( 530 hom. )

Consequence

ANKIB1
NM_019004.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0480

Publications

6 publications found

Variant links:

Genes affected

ANKIB1 (HGNC:22215): (ankyrin repeat and IBR domain containing 1) Predicted to enable ubiquitin conjugating enzyme binding activity and ubiquitin protein ligase activity. Predicted to be involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process; protein polyubiquitination; and ubiquitin-dependent protein catabolic process. Predicted to be part of ubiquitin ligase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ANKIB1 links:

KRIT1 (HGNC:1573): (KRIT1 ankyrin repeat containing) This gene encodes a protein containing four ankyrin repeats, a band 4.1/ezrin/radixin/moesin (FERM) domain, and multiple NPXY sequences. The encoded protein is localized in the nucleus and cytoplasm. It binds to integrin cytoplasmic domain-associated protein-1 alpha (ICAP1alpha), and plays a critical role in beta1-integrin-mediated cell proliferation. It associates with junction proteins and RAS-related protein 1A (Rap1A), which requires the encoded protein for maintaining the integrity of endothelial junctions. It is also a microtubule-associated protein and may play a role in microtubule targeting. Mutations in this gene result in cerebral cavernous malformations. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]

KRIT1 Gene-Disease associations (from GenCC):

cerebral cavernous malformation 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
famililal cerebral cavernous malformations
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRIT1 links:

ENSG00000289027 (HGNC:):

ENSG00000289027 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 (BayesDel_noAF=-0.74).

BP6

Variant 7-92245996-C-T is Benign according to our data. Variant chr7-92245996-C-T is described in ClinVar as Benign. ClinVar VariationId is 360905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ANKIB1	NM_019004.2 link	c.-614C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 20	ENST00000265742.8	NP_061877.1
ANKIB1	NM_019004.2 link	c.-614C>T	5_prime_UTR_variant	Exon 1 of 20	ENST00000265742.8	NP_061877.1
KRIT1	NM_194454.3 link	c.-627G>A	upstream_gene_variant		ENST00000394505.7	NP_919436.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ANKIB1	ENST00000265742.8 link	c.-614C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 20	1	NM_019004.2	ENSP00000265742.3
ANKIB1	ENST00000265742.8 link	c.-614C>T	5_prime_UTR_variant	Exon 1 of 20	1	NM_019004.2	ENSP00000265742.3
KRIT1	ENST00000394505.7 link	c.-627G>A	upstream_gene_variant		1	NM_194454.3	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1 link	c.-590G>A	upstream_gene_variant				ENSP00000510568.1
ENSG00000285953	ENST00000458493.6 link	c.-363G>A	upstream_gene_variant		4		ENSP00000396352.2

Frequencies

GnomAD3 genomes

AF:

0.0857

AC:

13037

AN:

152086

Hom.:

778

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0571

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.0819

Gnomad ASJ

AF:

0.0847

Gnomad EAS

AF:

0.358

Gnomad SAS

AF:

0.166

Gnomad FIN

AF:

0.0792

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0781

Gnomad OTH

AF:

0.0930

GnomAD4 exome

AF:

0.0967

AC:

7997

AN:

82698

Hom.:

530

Cov.:

AF XY:

0.105

AC XY:

4766

AN XY:

45508

show subpopulations

African (AFR)

AF:

0.0718

AC:

AN:

376

American (AMR)

AF:

0.111

AC:

AN:

388

Ashkenazi Jewish (ASJ)

AF:

0.0710

AC:

125

AN:

1760

East Asian (EAS)

AF:

0.430

AC:

104

AN:

242

South Asian (SAS)

AF:

0.150

AC:

2660

AN:

17680

European-Finnish (FIN)

AF:

0.0794

AC:

501

AN:

6308

Middle Eastern (MID)

AF:

0.138

AC:

AN:

320

European-Non Finnish (NFE)

AF:

0.0803

AC:

4110

AN:

51166

Other (OTH)

AF:

0.0859

AC:

383

AN:

4458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

326

652

979

1305

1631

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0857

AC:

13043

AN:

152204

Hom.:

779

Cov.:

AF XY:

0.0901

AC XY:

6703

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0572

AC:

2376

AN:

41546

American (AMR)

AF:

0.0818

AC:

1252

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0847

AC:

294

AN:

3472

East Asian (EAS)

AF:

0.358

AC:

1846

AN:

5152

South Asian (SAS)

AF:

0.166

AC:

801

AN:

4820

European-Finnish (FIN)

AF:

0.0792

AC:

840

AN:

10604

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0780

AC:

5306

AN:

67996

Other (OTH)

AF:

0.0925

AC:

195

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

611

1222

1833

2444

3055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<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:

0.0740

Hom.:

262

Bravo

AF:

0.0859

Asia WGS

AF:

0.205

AC:

713

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Angiokeratoma corporis diffusum with arteriovenous fistulas

Benign:1

Jan 13, 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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cerebral cavernous malformation

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.9

(source)

DANN

Benign

0.87

PhyloP100

-0.048

PromoterAI

-0.0056

Neutral

(source)

Mutation Taster

=298/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over