chr7-92199351-T-C

Variant names:

• chr7-92199351-T-C
• rs62467792
• ENST00000692281.1:c.2025+13844A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004912.4(KRIT1):​c.*1385A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 152,262 control chromosomes in the GnomAD database, including 981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (981 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: KRIT1 NM_004912.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.544
• Publications: 2 publications found

Genes affected

ENSG00000289027 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 7-92199351-T-C is Benign according to our data. Variant chr7-92199351-T-C is described in ClinVar as Benign. ClinVar VariationId is 360865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004912.4. 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_001350672.1		c.*1385A>G		3_prime_UTR	Exon 17 of 17	NP_001337601.1	O00522-1
	KRIT1	NM_001350673.1		c.*1385A>G		3_prime_UTR	Exon 18 of 18	NP_001337602.1	O00522-1
	KRIT1	NM_001350674.1		c.*1385A>G		3_prime_UTR	Exon 20 of 20	NP_001337603.1	O00522-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000289027	ENST00000692281.1		c.2025+13844A>G		intron	N/A	ENSP00000510568.1	A0A8I5KWQ7
	ENSG00000285953	ENST00000458493.6	TSL:4	c.2025+13844A>G		intron	N/A	ENSP00000396352.2	C9JD81
	KRIT1	ENST00000394507.5	TSL:5	c.*1385A>G		3_prime_UTR	Exon 20 of 20	ENSP00000378015.1	O00522-1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15226 AN: 152144 Hom.: 981 Cov.: 32

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.0806

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0266

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.101

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.100 AC: 15221 AN: 152262 Hom.: 981 Cov.: 32 AF XY: 0.0994 AC XY: 7398 AN XY: 74440

African (AFR) AF: 0.0261 AC: 1086 AN: 41562

American (AMR) AF: 0.0804 AC: 1230 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3472

East Asian (EAS) AF: 0.0266 AC: 138 AN: 5182

South Asian (SAS) AF: 0.104 AC: 500 AN: 4824

European-Finnish (FIN) AF: 0.155 AC: 1644 AN: 10600

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9695 AN: 68004

Other (OTH) AF: 0.102 AC: 215 AN: 2114

Alfa AF: 0.127 Hom.: 271

Bravo AF: 0.0899

Asia WGS AF: 0.0910 AC: 316 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Angiokeratoma corporis diffusum with arteriovenous fistulas (1)
-	-	1	Cerebral cavernous malformation (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs62467792; hg19: chr7-91828665;