11-57598275-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000062.3(SERPING1):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,557,632 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.16

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02144134).
• BP6: Variant 11-57598275-C-T is Benign according to our data. Variant chr11-57598275-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305016.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000992 (151/152270) while in subpopulation SAS AF= 0.00228 (11/4824). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3	c.5C>T	p.Ala2Val	missense_variant	2/8	ENST00000278407.9
SERPING1	NM_001032295.2	c.5C>T	p.Ala2Val	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9	c.5C>T	p.Ala2Val	missense_variant	2/8	1	NM_000062.3	P2

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152152 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00125 AC: 201 AN: 160658 Hom.: 1 AF XY: 0.00151 AC XY: 130 AN XY: 86220

Gnomad AFR exome AF: 0.000118

Gnomad AMR exome AF: 0.000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00358

Gnomad FIN exome AF: 0.000791

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.00135 AC: 1897 AN: 1405362 Hom.: 5 Cov.: 32 AF XY: 0.00137 AC XY: 954 AN XY: 693868

Gnomad4 AFR exome AF: 0.000187

Gnomad4 AMR exome AF: 0.000710

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00324

Gnomad4 FIN exome AF: 0.000961

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.000992 AC: 151 AN: 152270 Hom.: 0 Cov.: 31 AF XY: 0.000860 AC XY: 64 AN XY: 74454

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00111

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000235 AC: 1

ESP6500EA AF: 0.00107 AC: 9

ExAC AF: 0.000790 AC: 91

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2020	Reported in patients with angioedema in published literature; observed in the unaffected father of one patient (Gosswein et al., 2008; Rasmussen et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32896191, 31488451, 18758157) -

C1 inhibitor deficiency;C2717906:Hereditary angioedema type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

SERPING1 NM_000062.2 exon 2 p.Ala2Val (c.5C>T): This variant has been reported in the literature in 2 individuals with hereditary angioedema, segregating with disease in at least 2 affected family members (Gosswein 2008 PMID:18758157). However, this variant is present in 0.3% (84/23494) of South Asian alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs185342631). This variant is present in ClinVar (Variation ID:305016). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Hereditary angioedema type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.058	T;T;T;.;.;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.62	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.021	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.085	D
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D;D;D;D;.
Sift4G	Uncertain	0.044	D;D;D;D;D;D;D
Polyphen		0.99	.;D;.;.;.;D;.
Vest4		0.53, 0.52, 0.49, 0.70, 0.40
MVP		0.91
MPC		0.58
ClinPred		0.042	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.36
gMVP		0.65

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: rs185342631; hg19: chr11-57365748;