rs41278788

chr7-92225729-A-C

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.1245T>G(p.Ile415Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,543,714 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (8 hom.)
• Consequence: KRIT1 NM_194454.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.148

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=0.0065103173).
• BP6: Variant 7-92225729-A-C is Benign according to our data. Variant chr7-92225729-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 360884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92225729-A-C is described in Lovd as [Benign]. Variant chr7-92225729-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00185 (282/152260) while in subpopulation NFE AF= 0.00143 (97/68008). AF 95% confidence interval is 0.0012. There are 2 homozygotes in gnomad4. There are 190 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 282 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRIT1	NM_194454.3	c.1245T>G	p.Ile415Met	missense_variant	12/19	ENST00000394505.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRIT1	ENST00000394505.7	c.1245T>G	p.Ile415Met	missense_variant	12/19	1	NM_194454.3	P1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152142 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00239 AC: 601 AN: 251212 Hom.: 3 AF XY: 0.00231 AC XY: 314 AN XY: 135804

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0174

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00156 AC: 2177 AN: 1391454 Hom.: 8 Cov.: 26 AF XY: 0.00148 AC XY: 1033 AN XY: 696572

Gnomad4 AFR exome AF: 0.0000624

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000318

Gnomad4 FIN exome AF: 0.0152

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152260 Hom.: 2 Cov.: 32 AF XY: 0.00255 AC XY: 190 AN XY: 74440

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000714

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00223 AC: 271

EpiCase AF: 0.000981

EpiControl AF: 0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebral cavernous malformation Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Invitae	Nov 02, 2023	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

This 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. -

Angiokeratoma corporis diffusum with arteriovenous fistulas Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	3.9
Dann	Benign	0.89
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.75
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.80	T;T;.;.;.;T
MetaRNN	Benign	0.0065	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Benign	0.48	T
Polyphen		0.17	.;B;B;B;B;.
Vest4		0.18, 0.25, 0.21, 0.21, 0.15
MVP		0.60
MPC		0.31
ClinPred		0.0060	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.35

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: rs41278788; hg19: chr7-91855043;