rs2511988

chr11-57611697-A-Gchr11-57611697-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000062.3(SERPING1):c.1030-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,607,436 control chromosomes in the GnomAD database, including 350,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28314 hom., cov: 32)
  • Exomes 𝑓: 0.66 (321866 hom.)
• Consequence: SERPING1 NM_000062.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.10

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-57611697-A-G is Benign according to our data. Variant chr11-57611697-A-G is described in ClinVar as [Benign]. Clinvar id is 254785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-57611697-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3	c.1030-20A>G		intron_variant		ENST00000278407.9
SERPING1	NM_001032295.2	c.1030-20A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9	c.1030-20A>G		intron_variant		1	NM_000062.3	P2

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91352 AN: 151918 Hom.: 28299 Cov.: 32

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.689

Gnomad OTH AF: 0.608

GnomAD3 exomes AF: 0.581 AC: 145574 AN: 250716 Hom.: 44700 AF XY: 0.590 AC XY: 80022 AN XY: 135562

Gnomad AFR exome AF: 0.518

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.551

Gnomad EAS exome AF: 0.247

Gnomad SAS exome AF: 0.559

Gnomad FIN exome AF: 0.679

Gnomad NFE exome AF: 0.679

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.658 AC: 957618 AN: 1455400 Hom.: 321866 Cov.: 30 AF XY: 0.656 AC XY: 475249 AN XY: 724554

Gnomad4 AFR exome AF: 0.515

Gnomad4 AMR exome AF: 0.438

Gnomad4 ASJ exome AF: 0.546

Gnomad4 EAS exome AF: 0.242

Gnomad4 SAS exome AF: 0.562

Gnomad4 FIN exome AF: 0.683

Gnomad4 NFE exome AF: 0.697

Gnomad4 OTH exome AF: 0.627

GnomAD4 genome AF: 0.601 AC: 91407 AN: 152036 Hom.: 28314 Cov.: 32 AF XY: 0.596 AC XY: 44258 AN XY: 74308

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.525

Gnomad4 ASJ AF: 0.543

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.548

Gnomad4 FIN AF: 0.674

Gnomad4 NFE AF: 0.689

Gnomad4 OTH AF: 0.608

Alfa AF: 0.636 Hom.: 10700

Bravo AF: 0.582

Asia WGS AF: 0.417 AC: 1451 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary angioedema type 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	CeMIA	-	This variant is considered likely benign or benign based on one or more of the following criteria: allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (BA1), allele frequency is greater than expected for disorder (BS1), it is observed in a healthy adult individual (BS2), it is predicted to be benign by multiple in silico algorithms (BP4), it is found in a case with an alternate molecular basis for the disease (BP5) and/or reputable source recently reports variant as benign (BP6). -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 19200915, 18842294) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	7.6
Dann	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs2511988; hg19: chr11-57379170; COSMIC: COSV53542399;