2-113216619-G-C

Position:

• chr2-113216619-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003466.4(PAX8):​c.*1914C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 227,480 control chromosomes in the GnomAD database, including 11,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (8706 hom., cov: 32)
  • Exomes 𝑓: 0.27 (2805 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.206

Genes affected

PAX8 (HGNC:8622): (paired box 8) This gene encodes a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins that contain a paired box domain, an octapeptide, and a paired-type homeodomain. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

PAX8-AS1 (HGNC:49271): (PAX8 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-113216619-G-C is Benign according to our data. Variant chr2-113216619-G-C is described in ClinVar as [Benign]. Clinvar id is 330864.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX8	NM_003466.4	c.*1914C>G		3_prime_UTR_variant	12/12	ENST00000429538.8
PAX8	NM_013952.4	c.*1991C>G		3_prime_UTR_variant	12/12
PAX8	NM_013953.4	c.*1991C>G		3_prime_UTR_variant	10/10
PAX8	NM_013992.4	c.*1991C>G		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX8	ENST00000429538.8	c.*1914C>G		3_prime_UTR_variant	12/12	1	NM_003466.4	P1

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49090 AN: 151930 Hom.: 8695 Cov.: 32

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.265 AC: 19993 AN: 75432 Hom.: 2805 Cov.: 0 AF XY: 0.266 AC XY: 9262 AN XY: 34760

Gnomad4 AFR exome AF: 0.451

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.304

Gnomad4 SAS exome AF: 0.287

Gnomad4 FIN exome AF: 0.429

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.323 AC: 49144 AN: 152048 Hom.: 8706 Cov.: 32 AF XY: 0.325 AC XY: 24168 AN XY: 74348

Gnomad4 AFR AF: 0.474

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.211

Gnomad4 EAS AF: 0.270

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.268

Alfa AF: 0.298 Hom.: 930

Bravo AF: 0.315

Asia WGS AF: 0.324 AC: 1125 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs874898; hg19: chr2-113974196;