rs6066

Variant names:

• chr17-4933378-C-T
• rs6066
• NM_000173.7:c.774C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-4933378-C-T
• chr17-4933378-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000173.7(GP1BA):​c.774C>T​(p.Asn258Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,613,822 control chromosomes in the GnomAD database, including 1,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene GP1BA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.022 (62 hom., cov: 31)
  • Exomes 𝑓: 0.033 (938 hom.)
• Consequence: GP1BA NM_000173.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.46
• Publications: 5 publications found

Genes affected

GP1BA (HGNC:4439): (glycoprotein Ib platelet subunit alpha) Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein composed of a heterodimer, an alpha chain and a beta chain, that is linked by disulfide bonds. The Gp Ib functions as a receptor for von Willebrand factor (VWF). The complete receptor complex includes noncovalent association of the alpha and beta subunits with platelet glycoprotein IX and platelet glycoprotein V. The binding of the GP Ib-IX-V complex to VWF facilitates initial platelet adhesion to vascular subendothelium after vascular injury, and also initiates signaling events within the platelet that lead to enhanced platelet activation, thrombosis, and hemostasis. This gene encodes the alpha subunit. Mutations in this gene result in Bernard-Soulier syndromes and platelet-type von Willebrand disease. The coding region of this gene is known to contain a polymophic variable number tandem repeat (VNTR) domain that is associated with susceptibility to nonarteritic anterior ischemic optic neuropathy. [provided by RefSeq, Oct 2013]

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

CHRNE Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• congenital myasthenic syndrome 4A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 4C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for GP1BA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-4933378-C-T is Benign according to our data. Variant chr17-4933378-C-T is described in ClinVar as Benign. ClinVar VariationId is 255469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0221 (3366/152258) while in subpopulation NFE AF = 0.0346 (2355/68010). AF 95% confidence interval is 0.0335. There are 62 homozygotes in GnomAd4. There are 1545 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000173.7. 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
	GP1BA	NM_000173.7	MANE Select	c.774C>T	p.Asn258Asn	synonymous	Exon 2 of 2	NP_000164.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP1BA	ENST00000329125.6	TSL:1 MANE Select	c.774C>T	p.Asn258Asn	synonymous	Exon 2 of 2	ENSP00000329380.5	P07359
	CHRNE	ENST00000649830.1		c.-888+964G>A		intron	N/A	ENSP00000496907.1	A0A3B3IRM1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3366 AN: 152140 Hom.: 62 Cov.: 31

Gnomad AFR AF: 0.00814

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0238

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0218 AC: 5446 AN: 249270 AF XY: 0.0220

Gnomad AFR exome AF: 0.00555

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.0357

Gnomad OTH exome AF: 0.0198

GnomAD4 exome AF: 0.0326 AC: 47644 AN: 1461564 Hom.: 938 Cov.: 38 AF XY: 0.0314 AC XY: 22828 AN XY: 727070

African (AFR) AF: 0.00511 AC: 171 AN: 33480

American (AMR) AF: 0.0180 AC: 805 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 467 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00410 AC: 354 AN: 86256

European-Finnish (FIN) AF: 0.0143 AC: 766 AN: 53396

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0391 AC: 43465 AN: 1111734

Other (OTH) AF: 0.0264 AC: 1595 AN: 60370

GnomAD4 genome AF: 0.0221 AC: 3366 AN: 152258 Hom.: 62 Cov.: 31 AF XY: 0.0208 AC XY: 1545 AN XY: 74450

African (AFR) AF: 0.00812 AC: 337 AN: 41528

American (AMR) AF: 0.0238 AC: 364 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4828

European-Finnish (FIN) AF: 0.0108 AC: 115 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0346 AC: 2355 AN: 68010

Other (OTH) AF: 0.0256 AC: 54 AN: 2112

Alfa AF: 0.0316 Hom.: 240

Bravo AF: 0.0226

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0327

EpiControl AF: 0.0331

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.14
DANN	Benign	0.84
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs6066; hg19: chr17-4836673;