rs779465895

Variant names:

• chr7-92225840-G-C
• rs779465895
• NM_194454.3:c.1147-13C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-92225840-G-C
• chr7-92225840-G-A
• chr7-92225840-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_194454.3(KRIT1):​c.1147-13C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001201988: Studies have shown that this variant results in a new splice acceptor site, and produces a non-functional protein and/or introduces a premature termination codon (PMID:12810002)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRIT1 NM_194454.3 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0580
• Publications: 0 publications found

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289027 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001201988: Studies have shown that this variant results in a new splice acceptor site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 12810002).; SCV000852965: Functional analysis showed that it causes disrupted splicing and early protein termination (reported as IVS11-13 C>G in Marini et al 2003. PubMed ID: 12810002).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-92225840-G-C is Pathogenic according to our data. Variant chr7-92225840-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 590691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRIT1	NM_194454.3	MANE Select	c.1147-13C>G		intron	N/A	NP_919436.1	O00522-1
	KRIT1	NM_001350672.1		c.1147-13C>G		intron	N/A	NP_001337601.1	O00522-1
	KRIT1	NM_001350673.1		c.1147-13C>G		intron	N/A	NP_001337602.1	O00522-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRIT1	ENST00000394505.7	TSL:1 MANE Select	c.1147-13C>G		intron	N/A	ENSP00000378013.2	O00522-1
	ENSG00000289027	ENST00000692281.1		c.1147-13C>G		intron	N/A	ENSP00000510568.1	A0A8I5KWQ7
	ENSG00000285953	ENST00000458493.6	TSL:4	c.1147-13C>G		intron	N/A	ENSP00000396352.2	C9JD81

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Cerebral cavernous malformation (1)
1	-	-	KRIT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	12
DANN	Benign	0.54
PhyloP100		0.058
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -1
DS_AL_spliceai		0.94		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs779465895; hg19: chr7-91855154;