rs144799758

Variant names:

• chr14-70977749-C-G
• rs144799758
• NM_014982.3:c.1412C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014982.3(PCNX1):​c.1412C>G​(p.Thr471Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,614,014 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0086 (82 hom.)
• Consequence: PCNX1 NM_014982.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.832
• Publications: 7 publications found

Genes affected

PCNX1 (HGNC:19740): (pecanex 1) This gene encodes an evolutionarily conserved transmembrane protein similar to the pecanex protein in Drosophila. The fly protein is a component of the Notch signaling pathway, which functions in several developmental processes. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030736625).
• BP6: Variant 14-70977749-C-G is Benign according to our data. Variant chr14-70977749-C-G is described in ClinVar as Benign. ClinVar VariationId is 788802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 12 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014982.3. 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
	PCNX1	NM_014982.3	MANE Select	c.1412C>G	p.Thr471Ser	missense	Exon 6 of 36	NP_055797.2	Q96RV3-1
	PCNX1	NM_001308160.2		c.1412C>G	p.Thr471Ser	missense	Exon 6 of 34	NP_001295089.1	Q96RV3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNX1	ENST00000304743.7	TSL:1 MANE Select	c.1412C>G	p.Thr471Ser	missense	Exon 6 of 36	ENSP00000304192.2	Q96RV3-1
	PCNX1	ENST00000439984.7	TSL:1	c.1412C>G	p.Thr471Ser	missense	Exon 6 of 34	ENSP00000396617.3	Q96RV3-4
	PCNX1	ENST00000554879.5	TSL:1	n.1858C>G		non_coding_transcript_exon	Exon 6 of 10

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1633 AN: 152064 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00987

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00908 AC: 2282 AN: 251228 AF XY: 0.00932

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00933

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00860 AC: 12569 AN: 1461832 Hom.: 82 Cov.: 33 AF XY: 0.00890 AC XY: 6473 AN XY: 727206

African (AFR) AF: 0.0157 AC: 524 AN: 33478

American (AMR) AF: 0.00801 AC: 358 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 339 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.0155 AC: 1340 AN: 86248

European-Finnish (FIN) AF: 0.00232 AC: 124 AN: 53418

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5768

European-Non Finnish (NFE) AF: 0.00833 AC: 9264 AN: 1111986

Other (OTH) AF: 0.00906 AC: 547 AN: 60392

GnomAD4 genome AF: 0.0108 AC: 1636 AN: 152182 Hom.: 12 Cov.: 31 AF XY: 0.0104 AC XY: 771 AN XY: 74408

African (AFR) AF: 0.0141 AC: 585 AN: 41538

American (AMR) AF: 0.0113 AC: 173 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4814

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00988 AC: 672 AN: 67998

Other (OTH) AF: 0.0156 AC: 33 AN: 2110

Alfa AF: 0.0100 Hom.: 2

Bravo AF: 0.0116

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00927 AC: 1125

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0111

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.13
DANN	Benign	0.40
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.83
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.0080
Sift	Benign	0.76	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.068
MutPred		0.19		Loss of glycosylation at T471 (P = 0.0966)
MVP		0.043
MPC		0.092
ClinPred		0.0017	T
GERP RS		-1.4
Varity_R		0.019
gMVP		0.084
Mutation Taster		=99/1	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: rs144799758; hg19: chr14-71444466;