chr19-14480749-T-G

Position:

• chr19-14480749-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005716.4(GIPC1):​c.318A>C​(p.Lys106Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,434 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GIPC1 NM_005716.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.166

Genes affected

GIPC1 (HGNC:1226): (GIPC PDZ domain containing family member 1) GIPC1 is a scaffolding protein that regulates cell surface receptor expression and trafficking (Lee et al., 2008 [PubMed 18775991]).[supplied by OMIM, Apr 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIPC1	NM_005716.4	c.318A>C	p.Lys106Asn	missense_variant	5/9	ENST00000393033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIPC1	ENST00000393033.9	c.318A>C	p.Lys106Asn	missense_variant	5/9	1	NM_005716.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251052 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000137 AC: 2 AN: 1461434 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727054

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.318A>C (p.K106N) alteration is located in exon 5 (coding exon 2) of the GIPC1 gene. This alteration results from a A to C substitution at nucleotide position 318, causing the lysine (K) at amino acid position 106 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	-0.027
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.70	D
LIST_S2	Pathogenic	0.98	D;.;.;D;.;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.6	D;D;D;.;.;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;D;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.95	.;P;P;P;.;.;.
Vest4		0.79
MutPred		0.64		.;Loss of methylation at K106 (P = 0.0038);Loss of methylation at K106 (P = 0.0038);Loss of methylation at K106 (P = 0.0038);.;.;.;
MVP		0.63
MPC		0.26
ClinPred		0.98	D
GERP RS		-0.40
Varity_R		0.84
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs770234497; hg19: chr19-14591561;