chr11-94129334-A-G

Variant names:

• chr11-94129334-A-G
• rs770987950
• NM_015368.4:c.22A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015368.4(PANX1):​c.22A>G​(p.Thr8Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.0000055 (0 hom.)
• Consequence: PANX1 NM_015368.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.789
• Publications: 0 publications found

Genes affected

PANX1 (HGNC:8599): (pannexin 1) The protein encoded by this gene belongs to the innexin family. Innexin family members are the structural components of gap junctions. This protein and pannexin 2 are abundantly expressed in central nerve system (CNS) and are coexpressed in various neuronal populations. Studies in Xenopus oocytes suggest that this protein alone and in combination with pannexin 2 may form cell type-specific gap junctions with distinct properties. [provided by RefSeq, Jul 2008]

PANX1 Gene-Disease associations (from GenCC):

• oocyte maturation defect 7

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14756972).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANX1	NM_015368.4	c.22A>G	p.Thr8Ala	missense_variant	Exon 1 of 5	ENST00000227638.8	NP_056183.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANX1	ENST00000227638.8	c.22A>G	p.Thr8Ala	missense_variant	Exon 1 of 5	1	NM_015368.4	ENSP00000227638.3
PANX1	ENST00000436171.2	c.22A>G	p.Thr8Ala	missense_variant	Exon 1 of 5	1		ENSP00000411461.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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: 0.0000281 AC: 7 AN: 249328 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460012 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726116

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.000112 AC: 5 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110738

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22A>G (p.T8A) alteration is located in exon 1 (coding exon 1) of the PANX1 gene. This alteration results from a A to G substitution at nucleotide position 22, causing the threonine (T) at amino acid position 8 to be replaced by an alanine (A). 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	Benign	0.15
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.046	T;.
Eigen	Benign	-0.078
Eigen_PC	Benign	0.013
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		0.79
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.095
Sift	Benign	0.82	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.63	P;P
Vest4		0.13
MutPred		0.44		Loss of phosphorylation at T8 (P = 0.2026);Loss of phosphorylation at T8 (P = 0.2026);
MVP		0.34
MPC		0.20
ClinPred		0.15	T
GERP RS		4.2
PromoterAI		-0.026	Neutral
Varity_R		0.27
gMVP		0.78
Mutation Taster		=30/70	disease causing

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: rs770987950; hg19: chr11-93862500;