chr12-7064316-C-T

Variant names:

• chr12-7064316-C-T
• rs7965055
• NM_001734.5:c.441C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001734.5(C1S):​c.441C>T​(p.Cys147Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0772 in 1,613,732 control chromosomes in the GnomAD database, including 5,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (774 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4663 hom.)
• Consequence: C1S NM_001734.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.914
• Publications: 13 publications found

Genes affected

C1S (HGNC:1247): (complement C1s) This gene encodes a serine protease, which is a major constituent of the human complement subcomponent C1. C1s associates with two other complement components C1r and C1q in order to yield the first component of the serum complement system. Defects in this gene are the cause of selective C1s deficiency. [provided by RefSeq, Mar 2009]

C1S Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, periodontal type 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• complement component C1s deficiency

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Ehlers-Danlos syndrome, periodontal type 1

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• Ehlers-Danlos syndrome, periodontitis type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-7064316-C-T is Benign according to our data. Variant chr12-7064316-C-T is described in ClinVar as Benign. ClinVar VariationId is 402439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.914 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001734.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1S	NM_001734.5	MANE Select	c.441C>T	p.Cys147Cys	synonymous	Exon 5 of 12	NP_001725.1
	C1S	NM_201442.4		c.441C>T	p.Cys147Cys	synonymous	Exon 5 of 12	NP_958850.1
	C1S	NM_001346850.2		c.-61C>T		5_prime_UTR	Exon 4 of 11	NP_001333779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1S	ENST00000360817.10	TSL:1 MANE Select	c.441C>T	p.Cys147Cys	synonymous	Exon 5 of 12	ENSP00000354057.5
	C1S	ENST00000328916.7	TSL:1	c.441C>T	p.Cys147Cys	synonymous	Exon 5 of 12	ENSP00000328173.3
	C1S	ENST00000402681.7	TSL:1	c.-61C>T		5_prime_UTR	Exon 4 of 11	ENSP00000384171.3

Frequencies

GnomAD3 genomes AF: 0.0941 AC: 14298 AN: 152018 Hom.: 772 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0827

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0891

Gnomad FIN AF: 0.0608

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0740

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.0779 AC: 19589 AN: 251466 AF XY: 0.0790

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.0549

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.00163

Gnomad FIN exome AF: 0.0683

Gnomad NFE exome AF: 0.0787

Gnomad OTH exome AF: 0.0938

GnomAD4 exome AF: 0.0755 AC: 110334 AN: 1461596 Hom.: 4663 Cov.: 31 AF XY: 0.0762 AC XY: 55402 AN XY: 727116

African (AFR) AF: 0.152 AC: 5078 AN: 33474

American (AMR) AF: 0.0579 AC: 2588 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 3563 AN: 26126

East Asian (EAS) AF: 0.00118 AC: 47 AN: 39696

South Asian (SAS) AF: 0.0885 AC: 7630 AN: 86256

European-Finnish (FIN) AF: 0.0669 AC: 3574 AN: 53404

Middle Eastern (MID) AF: 0.167 AC: 964 AN: 5766

European-Non Finnish (NFE) AF: 0.0735 AC: 81676 AN: 1111772

Other (OTH) AF: 0.0864 AC: 5214 AN: 60380

GnomAD4 genome AF: 0.0941 AC: 14318 AN: 152136 Hom.: 774 Cov.: 32 AF XY: 0.0932 AC XY: 6930 AN XY: 74360

African (AFR) AF: 0.147 AC: 6089 AN: 41478

American (AMR) AF: 0.0826 AC: 1263 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 479 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5180

South Asian (SAS) AF: 0.0891 AC: 430 AN: 4824

European-Finnish (FIN) AF: 0.0608 AC: 643 AN: 10580

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0740 AC: 5033 AN: 68006

Other (OTH) AF: 0.108 AC: 228 AN: 2112

Alfa AF: 0.0856 Hom.: 1035

Bravo AF: 0.0975

Asia WGS AF: 0.0710 AC: 245 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.60
PhyloP100		0.91
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7965055; hg19: chr12-7171620; COSMIC: COSV61070998; COSMIC: COSV61070998;