rs28362941

Variant names:

• chr11-57597964-G-C
• rs28362941
• NM_000062.3:c.-23+242G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000062.3(SERPING1):​c.-23+242G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 457,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: SERPING1 NM_000062.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.764
• Publications: 2 publications found

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]

SERPING1 Gene-Disease associations (from GenCC):

• hereditary angioedema with C1Inh deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• C1 inhibitor deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary angioedema type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary angioedema type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0011 (167/151256) while in subpopulation AFR AF = 0.004 (165/41204). AF 95% confidence interval is 0.0035. There are 0 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 167 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.-23+242G>C		intron_variant	Intron 1 of 7	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.-307G>C		upstream_gene_variant			NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.-23+242G>C		intron_variant	Intron 1 of 7	1	NM_000062.3	ENSP00000278407.4

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 151142 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000484

GnomAD4 exome AF: 0.000183 AC: 56 AN: 305912 Hom.: 1 Cov.: 0 AF XY: 0.000190 AC XY: 30 AN XY: 157600

African (AFR) AF: 0.00553 AC: 50 AN: 9038

American (AMR) AF: 0.000151 AC: 2 AN: 13278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9522

East Asian (EAS) AF: 0.00 AC: 0 AN: 21868

South Asian (SAS) AF: 0.00 AC: 0 AN: 23168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1358

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 180718

Other (OTH) AF: 0.000218 AC: 4 AN: 18348

GnomAD4 genome AF: 0.00110 AC: 167 AN: 151256 Hom.: 0 Cov.: 30 AF XY: 0.00108 AC XY: 80 AN XY: 73894

African (AFR) AF: 0.00400 AC: 165 AN: 41204

American (AMR) AF: 0.0000659 AC: 1 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67732

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000714 Hom.: 0

Bravo AF: 0.00155

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.75
PhyloP100		0.76
PromoterAI		-0.012	Neutral

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: rs28362941; hg19: chr11-57365437;