2-172427775-C-G

Position:

• chr2-172427775-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001394928.1(ITGA6):​c.-14C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,580,184 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (20 hom.)
• Consequence: ITGA6 NM_001394928.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.666

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-172427775-C-G is Benign according to our data. Variant chr2-172427775-C-G is described in ClinVar as [Benign]. Clinvar id is 332354.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.003 (457/152228) while in subpopulation SAS AF= 0.00849 (41/4828). AF 95% confidence interval is 0.00643. There are 2 homozygotes in gnomad4. There are 212 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA6	NM_000210.4	c.-14C>G		5_prime_UTR_variant	1/26	ENST00000684293.1
ITGA6	NM_001394928.1	c.-14C>G		5_prime_UTR_variant	1/26	ENST00000442250.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA6	ENST00000442250.6	c.-14C>G		5_prime_UTR_variant	1/26	5	NM_001394928.1
ITGA6	ENST00000684293.1	c.-14C>G		5_prime_UTR_variant	1/26		NM_000210.4	P3
	ENST00000441212.1	n.557G>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152116 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00342 AC: 665 AN: 194632 Hom.: 4 AF XY: 0.00408 AC XY: 442 AN XY: 108442

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.000578

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00694

Gnomad FIN exome AF: 0.00197

Gnomad NFE exome AF: 0.00434

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00353 AC: 5037 AN: 1427956 Hom.: 20 Cov.: 34 AF XY: 0.00373 AC XY: 2647 AN XY: 709208

Gnomad4 AFR exome AF: 0.000740

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.000475

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00708

Gnomad4 FIN exome AF: 0.00194

Gnomad4 NFE exome AF: 0.00363

Gnomad4 OTH exome AF: 0.00388

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152228 Hom.: 2 Cov.: 33 AF XY: 0.00285 AC XY: 212 AN XY: 74436

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00397

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00175 Hom.: 1

Bravo AF: 0.00309

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.45
CADD	Benign	13
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs144341070; hg19: chr2-173292503;