chr2-172504503-A-G

Position:

• chr2-172504503-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000210.4(ITGA6):​c.*435A>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 0.49 in 328,542 control chromosomes in the GnomAD database, including 42,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21041 hom., cov: 33)
  • Exomes 𝑓: 0.47 (21462 hom.)
• Consequence: ITGA6 NM_000210.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.165

Genes affected

ITGA6 (HGNC:6142): (integrin subunit alpha 6) The gene encodes a member of the integrin alpha chain family of proteins. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain that function in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 6 subunit. This subunit may associate with a beta 1 or beta 4 subunit to form an integrin that interacts with extracellular matrix proteins including members of the laminin family. The alpha 6 beta 4 integrin may promote tumorigenesis, while the alpha 6 beta 1 integrin may negatively regulate erbB2/HER2 signaling. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

PDK1-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-172504503-A-G is Benign according to our data. Variant chr2-172504503-A-G is described in ClinVar as [Benign]. Clinvar id is 332395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA6	NM_001394928.1	c.*251A>G		3_prime_UTR_variant	26/26	ENST00000442250.6	NP_001381857.1
ITGA6	NM_000210.4	c.*435A>G		3_prime_UTR_variant	26/26	ENST00000684293.1	NP_000201.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA6	ENST00000442250.6	c.*251A>G		3_prime_UTR_variant	26/26	5	NM_001394928.1	ENSP00000406694.1
ITGA6	ENST00000684293.1	c.*435A>G		3_prime_UTR_variant	26/26		NM_000210.4	ENSP00000508249.1

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77449 AN: 151942 Hom.: 21006 Cov.: 33

Gnomad AFR AF: 0.653

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.872

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.484

GnomAD4 exome AF: 0.472 AC: 83282 AN: 176482 Hom.: 21462 Cov.: 3 AF XY: 0.478 AC XY: 44366 AN XY: 92778

Gnomad4 AFR exome AF: 0.661

Gnomad4 AMR exome AF: 0.571

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.876

Gnomad4 SAS exome AF: 0.623

Gnomad4 FIN exome AF: 0.489

Gnomad4 NFE exome AF: 0.394

Gnomad4 OTH exome AF: 0.463

GnomAD4 genome AF: 0.510 AC: 77548 AN: 152060 Hom.: 21041 Cov.: 33 AF XY: 0.519 AC XY: 38601 AN XY: 74332

Gnomad4 AFR AF: 0.654

Gnomad4 AMR AF: 0.529

Gnomad4 ASJ AF: 0.388

Gnomad4 EAS AF: 0.872

Gnomad4 SAS AF: 0.631

Gnomad4 FIN AF: 0.508

Gnomad4 NFE AF: 0.390

Gnomad4 OTH AF: 0.489

Alfa AF: 0.408 Hom.: 21400

Bravo AF: 0.520

Asia WGS AF: 0.739 AC: 2567 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Junctional epidermolysis bullosa with pyloric atresia 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	-0.73
CADD	Benign	13
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs17664; hg19: chr2-173369231;