2-126693911-T-C

Variant names:

• chr2-126693911-T-C
• rs753718670
• NM_002101.5:c.154T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002101.5(GYPC):​c.154T>C​(p.Ser52Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GYPC NM_002101.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.801
• Publications: 1 publications found

Genes affected

GYPC (HGNC:4704): (glycophorin C (Gerbich blood group)) Glycophorin C (GYPC) is an integral membrane glycoprotein. It is a minor species carried by human erythrocytes, but plays an important role in regulating the mechanical stability of red cells. A number of glycophorin C mutations have been described. The Gerbich and Yus phenotypes are due to deletion of exon 3 and 2, respectively. The Webb and Duch antigens, also known as glycophorin D, result from single point mutations of the glycophorin C gene. The glycophorin C protein has very little homology with glycophorins A and B. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

GYPC Gene-Disease associations (from GenCC):

• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06076026).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002101.5. 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
	GYPC	NM_002101.5	MANE Select	c.154T>C	p.Ser52Pro	missense	Exon 3 of 4	NP_002092.1	P04921-1
	GYPC	NM_016815.4		c.97T>C	p.Ser33Pro	missense	Exon 2 of 3	NP_058131.1	P04921-3
	GYPC	NM_001256584.2		c.91T>C	p.Ser31Pro	missense	Exon 4 of 5	NP_001243513.1	P04921-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYPC	ENST00000259254.9	TSL:1 MANE Select	c.154T>C	p.Ser52Pro	missense	Exon 3 of 4	ENSP00000259254.4	P04921-1
	GYPC	ENST00000409836.3	TSL:1	c.97T>C	p.Ser33Pro	missense	Exon 2 of 3	ENSP00000386904.3	P04921-3
	GYPC	ENST00000356887.12	TSL:1	c.91T>C	p.Ser31Pro	missense	Exon 4 of 5	ENSP00000349354.7	P04921-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251350 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460108 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726494

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.000112 AC: 5 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110408

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.0000656 AC: 1 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.0
DANN	Benign	0.70
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00080	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.00096	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.80
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.018
Sift	Benign	0.15	T
Sift4G	Benign	0.29	T
Polyphen		0.54	P
Vest4		0.19
MutPred		0.20		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.040
MPC		0.0046
ClinPred		0.031	T
GERP RS		-2.2
Varity_R		0.041
gMVP		0.097
Mutation Taster		=95/5	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: rs753718670; hg19: chr2-127451487;