chr20-21706706-G-A

Variant names:

• chr20-21706706-G-A
• rs17861031
• NM_001257096.2:c.555G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001257096.2(PAX1):​c.555G>A​(p.Lys185Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,613,484 control chromosomes in the GnomAD database, including 1,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (565 hom., cov: 32)
  • Exomes 𝑓: 0.020 (942 hom.)
• Consequence: PAX1 NM_001257096.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.23
• Publications: 11 publications found

Genes affected

PAX1 (HGNC:8615): (paired box 1) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. This gene plays a role in pattern formation during embryogenesis and may be essential for development of the vertebral column. This gene is silenced by methylation in ovarian and cervical cancers and may be a tumor suppressor gene. Mutations in this gene are also associated with vertebral malformations. [provided by RefSeq, Mar 2012]

PAX1 Gene-Disease associations (from GenCC):

• otofaciocervical syndrome 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 20-21706706-G-A is Benign according to our data. Variant chr20-21706706-G-A is described in ClinVar as Benign. ClinVar VariationId is 1168083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257096.2. 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
	PAX1	NM_001257096.2	MANE Select	c.555G>A	p.Lys185Lys	synonymous	Exon 2 of 5	NP_001244025.1	A0A087WXV5
	PAX1	NM_006192.5		c.555G>A	p.Lys185Lys	synonymous	Exon 2 of 5	NP_006183.2	P15863-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX1	ENST00000613128.5	TSL:1 MANE Select	c.555G>A	p.Lys185Lys	synonymous	Exon 2 of 5	ENSP00000481334.1	A0A087WXV5
	PAX1	ENST00000398485.6	TSL:5	c.555G>A	p.Lys185Lys	synonymous	Exon 2 of 5	ENSP00000381499.2	P15863-1
	PAX1	ENST00000444366.2	TSL:2	c.483G>A	p.Lys161Lys	synonymous	Exon 1 of 4	ENSP00000410355.2	P15863-2

Frequencies

GnomAD3 genomes AF: 0.0554 AC: 8434 AN: 152208 Hom.: 565 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0425

GnomAD2 exomes AF: 0.0294 AC: 7380 AN: 250862 AF XY: 0.0261

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.00643

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0201 AC: 29432 AN: 1461158 Hom.: 942 Cov.: 32 AF XY: 0.0197 AC XY: 14337 AN XY: 726924

African (AFR) AF: 0.149 AC: 4980 AN: 33480

American (AMR) AF: 0.0183 AC: 819 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 128 AN: 26134

East Asian (EAS) AF: 0.143 AC: 5660 AN: 39700

South Asian (SAS) AF: 0.0155 AC: 1340 AN: 86258

European-Finnish (FIN) AF: 0.00731 AC: 385 AN: 52698

Middle Eastern (MID) AF: 0.0154 AC: 89 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14563 AN: 1112002

Other (OTH) AF: 0.0243 AC: 1468 AN: 60394

GnomAD4 genome AF: 0.0554 AC: 8444 AN: 152326 Hom.: 565 Cov.: 32 AF XY: 0.0534 AC XY: 3980 AN XY: 74480

African (AFR) AF: 0.150 AC: 6254 AN: 41576

American (AMR) AF: 0.0255 AC: 390 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.123 AC: 633 AN: 5162

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4826

European-Finnish (FIN) AF: 0.00584 AC: 62 AN: 10624

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 911 AN: 68036

Other (OTH) AF: 0.0416 AC: 88 AN: 2114

Alfa AF: 0.0326 Hom.: 123

Bravo AF: 0.0615

Asia WGS AF: 0.0690 AC: 240 AN: 3478

EpiCase AF: 0.0126

EpiControl AF: 0.0126

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	PAX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.0
DANN	Benign	0.35
PhyloP100		1.2
PromoterAI		0.015	Neutral
Mutation Taster		=97/3	polymorphism (auto)

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: rs17861031; hg19: chr20-21687344; COSMIC: COSV68272653; COSMIC: COSV68272653;