rs41278788

Variant names:

• chr7-92225729-A-C
• rs41278788
• NM_194454.3:c.1245T>G
• KRIT1 p.Ile415Met

Your query was ambiguous. Multiple possible variants found:

• chr7-92225729-A-C
• chr7-92225729-A-G
• chr7-92225729-A-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I415F) has been classified as Uncertain significance.

• 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:8
• Conservation: PhyloP100: -0.148
• Publications: 2 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), Ambry Genetics, G2P
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289027 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 360884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 282 AD gene.

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.1245T>G	p.Ile415Met	missense	Exon 12 of 19	NP_919436.1	O00522-1
	KRIT1	NM_001350672.1		c.1245T>G	p.Ile415Met	missense	Exon 10 of 17	NP_001337601.1	O00522-1
	KRIT1	NM_001350673.1		c.1245T>G	p.Ile415Met	missense	Exon 11 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.1245T>G	p.Ile415Met	missense	Exon 12 of 19	ENSP00000378013.2	O00522-1
	ENSG00000289027	ENST00000692281.1		c.1245T>G	p.Ile415Met	missense	Exon 12 of 26	ENSP00000510568.1	A0A8I5KWQ7
	ENSG00000285953	ENST00000458493.6	TSL:4	c.1245T>G	p.Ile415Met	missense	Exon 11 of 20	ENSP00000396352.2	C9JD81

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

GnomAD2 exomes AF: 0.00239 AC: 601 AN: 251212 AF XY: 0.00231

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 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

African (AFR) AF: 0.0000624 AC: 2 AN: 32074

American (AMR) AF: 0.0000896 AC: 4 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25726

East Asian (EAS) AF: 0.00 AC: 0 AN: 39320

South Asian (SAS) AF: 0.000318 AC: 27 AN: 84790

European-Finnish (FIN) AF: 0.0152 AC: 811 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5052

European-Non Finnish (NFE) AF: 0.00119 AC: 1244 AN: 1048510

Other (OTH) AF: 0.00152 AC: 88 AN: 58020

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

African (AFR) AF: 0.000217 AC: 9 AN: 41568

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000714

EpiCase AF: 0.000981

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cerebral cavernous malformation (3)
-	-	2	not provided (2)
-	-	1	Angiokeratoma corporis diffusum with arteriovenous fistulas (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.75
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.15
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.027
Sift	Benign	0.082	T
Sift4G	Benign	0.16	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.35
Mutation Taster		=95/5	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41278788;

hg19: chr7-91855043;