rs121912761

Variant names:

• chr2-126656303-C-A
• rs121912761
• NM_002101.5:c.40C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-126656303-C-A
• chr2-126656303-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_002101.5(GYPC):​c.40C>A​(p.Leu14Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,440,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L14F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: GYPC NM_002101.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 5 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06286961).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYPC	NM_002101.5	c.40C>A	p.Leu14Ile	missense_variant	Exon 1 of 4	ENST00000259254.9	NP_002092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYPC	ENST00000259254.9	c.40C>A	p.Leu14Ile	missense_variant	Exon 1 of 4	1	NM_002101.5	ENSP00000259254.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 203482 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1440450 Hom.: 0 Cov.: 32 AF XY: 0.00000419 AC XY: 3 AN XY: 715248

African (AFR) AF: 0.00 AC: 0 AN: 32814

American (AMR) AF: 0.00 AC: 0 AN: 42718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.00 AC: 0 AN: 38248

South Asian (SAS) AF: 0.00 AC: 0 AN: 83792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103228

Other (OTH) AF: 0.00 AC: 0 AN: 59334

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.35
DANN	Benign	0.85
DEOGEN2	Benign	0.0088	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.22	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.024
Sift	Uncertain	0.018	D;T
Sift4G	Benign	0.27	T;T
Polyphen		0.61	P;.
Vest4		0.098
MutPred		0.10		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.040
MPC		0.011
ClinPred		0.16	T
GERP RS		0.91
PromoterAI		-0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.042
Mutation Taster		=98/2	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: rs121912761; hg19: chr2-127413879;