11-57602130-A-TCAGTGTCGTG

Position:

• chr11-57602130-A-TCAGTGTCGTG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000062.3(SERPING1):​c.646delinsTCAGTGTCGTG​(p.Lys216SerfsTer4) variant causes a stop gained, frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERPING1 NM_000062.3 stop_gained, frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.21

Genes affected

SERPING1 (HGNC:1228): (serpin family G member 1) This gene encodes a highly glycosylated plasma protein involved in the regulation of the complement cascade. Its encoded protein, C1 inhibitor, inhibits activated C1r and C1s of the first complement component and thus regulates complement activation. It is synthesized in the liver, and its deficiency is associated with hereditary angioneurotic oedema (HANE). Alternative splicing results in multiple transcript variants encoding the same isoform. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57602130-A-TCAGTGTCGTG is Pathogenic according to our data. Variant chr11-57602130-A-TCAGTGTCGTG is described in ClinVar as [Pathogenic]. Clinvar id is 487526.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.646delinsTCAGTGTCGTG	p.Lys216SerfsTer4	stop_gained, frameshift_variant	4/8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.646delinsTCAGTGTCGTG	p.Lys216SerfsTer4	stop_gained, frameshift_variant	3/7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.646delinsTCAGTGTCGTG	p.Lys216SerfsTer4	stop_gained, frameshift_variant	4/8	1	NM_000062.3	ENSP00000278407	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary angioedema type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 11, 2021

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554995271; hg19: chr11-57369603;