3-186720217-T-A

Position:

• chr3-186720217-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001102416.3(KNG1):​c.306+2T>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KNG1 NM_001102416.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.93

Genes affected

KNG1 (HGNC:6383): (kininogen 1) This gene uses alternative splicing to generate two different proteins- high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal activity. In contrast to HMWK, LMWK is not involved in blood coagulation. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduces or depletes angiotensin converting enzyme 2 (ACE2), which results in an increase in levels of des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin that is associated with lung injury and inflammation. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2020]

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.056847546 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.9, offset of -26, new splice context is: actGTgagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-186720217-T-A is Pathogenic according to our data. Variant chr3-186720217-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2578035.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-186720217-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.306+2T>A		splice_donor_variant		ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.306+2T>A		splice_donor_variant			NP_000884.1
KNG1	NM_001166451.2	c.306+2T>A		splice_donor_variant			NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.306+2T>A		splice_donor_variant			NM_001102416.3	ENSP00000493985
HRG-AS1	ENST00000630178.2	n.136-1648A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.93e-7 AC: 1 AN: 1442334 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 718968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

High molecular weight kininogen deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz

Sep 04, 2023

This canonical splice site variant, NM_001102416.3(KNG1):c.306+2T>A, was detected in a homozygous individual deficient in high-molecular-weight kininogen (<2% HK activity, <1% HK antigen, prolonged aPTT) (PMID: 36700498) using Sanger Sequncing. Gros deletions and insertions in the corresponding area were excluded using ddPCR. The two children of the index case are heterozygous carriers of the variant and show slightly decreased HK antigen levels (37-44%). The variant has otherwise not been described in the literature and is not included in the dbSNP, which is why a very low MAF can be assumed. Predictions tools predict pathogenicity. Due to the location of the variant, a combined deficiency of HK and low-molecular-weight kininogen is likely. The base exchange affects the canonical, highly conserved donor splice site of IVS 2. Therefore, we classified this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	31
DANN	Uncertain	0.97
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.76	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: -28
DS_DL_spliceai		0.98		Position offset: -2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-186438006;