Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_194454.3(KRIT1):c.1140G>A(p.Thr380Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,610,028 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 9 hom. )

Consequence

KRIT1
NM_194454.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.55

Publications

1 publications found

Variant links:

Genes affected

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 7-92226532-C-T is Benign according to our data. Variant chr7-92226532-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.55 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00178 (271/152062) while in subpopulation NFE AF = 0.00243 (165/67960). AF 95% confidence interval is 0.00213. There are 1 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 271 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194454.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KRIT1	NM_194454.3	MANE Select	c.1140G>A	p.Thr380Thr	synonymous	Exon 11 of 19	NP_919436.1
KRIT1	NM_001350672.1		c.1140G>A	p.Thr380Thr	synonymous	Exon 9 of 17	NP_001337601.1
KRIT1	NM_001350673.1		c.1140G>A	p.Thr380Thr	synonymous	Exon 10 of 18	NP_001337602.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KRIT1	ENST00000394505.7	TSL:1 MANE Select	c.1140G>A	p.Thr380Thr	synonymous	Exon 11 of 19	ENSP00000378013.2
ENSG00000289027	ENST00000692281.1		c.1140G>A	p.Thr380Thr	synonymous	Exon 11 of 26	ENSP00000510568.1
ENSG00000285953	ENST00000458493.6	TSL:4	c.1140G>A	p.Thr380Thr	synonymous	Exon 10 of 20	ENSP00000396352.2

Frequencies

GnomAD3 genomes

AF:

0.00178

AC:

271

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00312

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00143

AC:

359

AN:

251066

AF XY:

0.00142

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00366

Gnomad NFE exome

AF:

0.00227

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.00251

AC:

3656

AN:

1457966

Hom.:

Cov.:

AF XY:

0.00245

AC XY:

1775

AN XY:

725628

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33400

American (AMR)

AF:

0.000447

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00390

AC:

208

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00300

AC:

3326

AN:

1108602

Other (OTH)

AF:

0.00148

AC:

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

163

326

490

653

816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<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:

0.00178

AC:

271

AN:

152062

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41492

American (AMR)

AF:

0.000458

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000208

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00312

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00243

AC:

165

AN:

67960

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00174

Hom.:

Bravo

AF:

0.00169

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cerebral cavernous malformation (2)

not specified (2)

Angiokeratoma corporis diffusum with arteriovenous fistulas (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.44

PhyloP100

1.6

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs140009885

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over