rs148836047

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_194454.3(KRIT1):​c.1752C>T​(p.Ile584Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,607,498 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

KRIT1
NM_194454.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0150
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
Variant 7-92213958-G-A is Benign according to our data. Variant chr7-92213958-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92213958-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.015 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000112 (17/152210) while in subpopulation SAS AF= 0.000207 (1/4824). AF 95% confidence interval is 0.000124. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KRIT1NM_194454.3 linkuse as main transcriptc.1752C>T p.Ile584Ile synonymous_variant 16/19 ENST00000394505.7 NP_919436.1 O00522-1A4D1F7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KRIT1ENST00000394505.7 linkuse as main transcriptc.1752C>T p.Ile584Ile synonymous_variant 16/191 NM_194454.3 ENSP00000378013.2 O00522-1
ENSG00000289027ENST00000692281.1 linkuse as main transcriptc.1752C>T p.Ile584Ile synonymous_variant 16/26 ENSP00000510568.1 A0A8I5KWQ7
ENSG00000285953ENST00000458493.6 linkuse as main transcriptc.1752C>T p.Ile584Ile synonymous_variant 15/204 ENSP00000396352.2 C9JD81

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152092
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000163
AC:
41
AN:
251296
Hom.:
0
AF XY:
0.000184
AC XY:
25
AN XY:
135814
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000334
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000203
AC:
295
AN:
1455288
Hom.:
1
Cov.:
28
AF XY:
0.000204
AC XY:
148
AN XY:
724396
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000228
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000252
Gnomad4 OTH exome
AF:
0.0000665
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000230
Hom.:
0
Bravo
AF:
0.000136
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 06, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Benign:1
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Cerebral cavernous malformation Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 02, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
CADD
Benign
9.6
DANN
Benign
0.74

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

LitVar

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

Other links and lift over

dbSNP: rs148836047; hg19: chr7-91843272; COSMIC: COSV60668467; API