11-57597638-GC-GCC

Variant names:

• chr11-57597638-G-GC
• rs28362939
• ENST00000619430.2:c.-99dupC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000619430.2(SERPING1):​c.-99dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 151,452 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (8 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SERPING1 ENST00000619430.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.232
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen
• 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 -10 ACMG points.

• BP6: Variant 11-57597638-G-GC is Benign according to our data. Variant chr11-57597638-G-GC is described in ClinVar as Likely_benign. ClinVar VariationId is 305009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00718 (1088/151452) while in subpopulation AFR AF = 0.0242 (1000/41260). AF 95% confidence interval is 0.023. There are 8 homozygotes in GnomAd4. There are 525 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1088 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000619430.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPING1	NM_000062.3	MANE Select	c.-107_-106insC		upstream_gene	N/A	NP_000053.2	P05155-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPING1	ENST00000619430.2	TSL:1	c.-99dupC		5_prime_UTR	Exon 1 of 7	ENSP00000478572.2	A0A087WUD9
	SERPING1	ENST00000879467.1		c.-99dupC		5_prime_UTR	Exon 1 of 9	ENSP00000549526.1
	SERPING1	ENST00000879468.1		c.-625dupC		5_prime_UTR	Exon 1 of 7	ENSP00000549527.1

Frequencies

GnomAD3 genomes AF: 0.00718 AC: 1086 AN: 151340 Hom.: 6 Cov.: 30

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00297

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000777

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.00579

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 266 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 190

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 228

Other (OTH) AF: 0.00 AC: 0 AN: 10

GnomAD4 genome AF: 0.00718 AC: 1088 AN: 151452 Hom.: 8 Cov.: 30 AF XY: 0.00709 AC XY: 525 AN XY: 74028

African (AFR) AF: 0.0242 AC: 1000 AN: 41260

American (AMR) AF: 0.00297 AC: 45 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000779 AC: 4 AN: 5134

South Asian (SAS) AF: 0.00209 AC: 10 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10534

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

European-Non Finnish (NFE) AF: 0.000251 AC: 17 AN: 67820

Other (OTH) AF: 0.00573 AC: 12 AN: 2096

Alfa AF: 0.0000545 Hom.: 0

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary angioneurotic edema (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

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: rs28362939; hg19: chr11-57365111;