rs34358665

chr7-92242059-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194454.3(KRIT1):c.77G>A(p.Arg26Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00133 in 1,576,640 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: KRIT1 NM_194454.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.48

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014538407).
• BP6: Variant 7-92242059-C-T is Benign according to our data. Variant chr7-92242059-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 360890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92242059-C-T is described in Lovd as [Likely_benign]. Variant chr7-92242059-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000909 (138/151844) while in subpopulation NFE AF= 0.00143 (97/67958). AF 95% confidence interval is 0.0012. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRIT1	NM_194454.3	c.77G>A	p.Arg26Gln	missense_variant	4/19	ENST00000394505.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRIT1	ENST00000394505.7	c.77G>A	p.Arg26Gln	missense_variant	4/19	1	NM_194454.3	P1

Frequencies

GnomAD3 genomes AF: 0.000909 AC: 138 AN: 151844 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00104 AC: 261 AN: 251236 Hom.: 0 AF XY: 0.00105 AC XY: 143 AN XY: 135792

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00137 AC: 1955 AN: 1424796 Hom.: 4 Cov.: 26 AF XY: 0.00132 AC XY: 939 AN XY: 711434

Gnomad4 AFR exome AF: 0.000490

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.000909 AC: 138 AN: 151844 Hom.: 0 Cov.: 32 AF XY: 0.000823 AC XY: 61 AN XY: 74126

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.000591

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00240

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.000888

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00101 AC: 122

EpiCase AF: 0.00142

EpiControl AF: 0.000949

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebral cavernous malformation Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Angiokeratoma corporis diffusum with arteriovenous fistulas Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

KRIT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	22
Dann	Pathogenic	1.0
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;.;.;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.49	T
Polyphen		0.91	.;P;P;P;P;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.21, 0.22, 0.22, 0.21, 0.18
MVP		0.87
MPC		0.35
ClinPred		0.024	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.30

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

Other links and lift over

dbSNP: rs34358665; hg19: chr7-91871373; COSMIC: COSV56059748; COSMIC: COSV56059748;