NM_194454.3:c.301G>A

Variant names:

• chr7-92237721-C-T
• rs1057521140
• NM_194454.3:c.301G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_194454.3(KRIT1):​c.301G>A​(p.Gly101Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G101V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRIT1 NM_194454.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.80
• 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: Uncertain_significance. The variant received 5 ACMG points.

• 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 7-92237721-C-T is Pathogenic according to our data. Variant chr7-92237721-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 381675.

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.301G>A	p.Gly101Arg	missense	Exon 6 of 19	NP_919436.1	O00522-1
	KRIT1	NM_001350672.1		c.301G>A	p.Gly101Arg	missense	Exon 4 of 17	NP_001337601.1	O00522-1
	KRIT1	NM_001350673.1		c.301G>A	p.Gly101Arg	missense	Exon 5 of 18	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.301G>A	p.Gly101Arg	missense	Exon 6 of 19	ENSP00000378013.2	O00522-1
	ENSG00000289027	ENST00000692281.1		c.301G>A	p.Gly101Arg	missense	Exon 6 of 26	ENSP00000510568.1	A0A8I5KWQ7
	ENSG00000285953	ENST00000458493.6	TSL:4	c.301G>A	p.Gly101Arg	missense	Exon 5 of 20	ENSP00000396352.2	C9JD81

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebral cavernous malformation (1)
1	-	-	KRIT1-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	2.0	M
PhyloP100		6.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.49
Sift	Benign	0.040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.41		Gain of loop (P = 0.0166)
MVP		0.91
MPC		1.0
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.33
gMVP		0.68
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.84		Position offset: -2
DS_AL_spliceai		0.55		Position offset: 38

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

Other links and lift over

dbSNP: rs1057521140; hg19: chr7-91867035;