2-172427667-C-T

Variant names:

• chr2-172427667-C-T
• rs373890886
• NM_001394928.1:c.-122C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000210.4(ITGA6):​c.-122C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000098 in 1,326,360 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (1 hom.)
• Consequence: ITGA6 NM_000210.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.583
• Publications: 0 publications found

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]

ITGA6 Gene-Disease associations (from GenCC):

• junctional epidermolysis bullosa with pyloric atresia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa, junctional 6, with pyloric atresia

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ENSG00000226963 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000210.4. 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
	ITGA6	NM_001394928.1	MANE Plus Clinical	c.-122C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 26	NP_001381857.1	P23229-1
	ITGA6	NM_000210.4	MANE Select	c.-122C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 26	NP_000201.2	P23229-2
	ITGA6	NM_001394928.1	MANE Plus Clinical	c.-122C>T		5_prime_UTR	Exon 1 of 26	NP_001381857.1	P23229-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA6	ENST00000442250.6	TSL:5 MANE Plus Clinical	c.-122C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 26	ENSP00000406694.1	P23229-1
	ITGA6	ENST00000684293.1	MANE Select	c.-122C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 26	ENSP00000508249.1	P23229-2
	ITGA6	ENST00000442250.6	TSL:5 MANE Plus Clinical	c.-122C>T		5_prime_UTR	Exon 1 of 26	ENSP00000406694.1	P23229-1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000903 AC: 106 AN: 1174050 Hom.: 1 Cov.: 34 AF XY: 0.000110 AC XY: 62 AN XY: 565710

African (AFR) AF: 0.00 AC: 0 AN: 22822

American (AMR) AF: 0.00 AC: 0 AN: 8320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15418

East Asian (EAS) AF: 0.000812 AC: 21 AN: 25878

South Asian (SAS) AF: 0.00138 AC: 59 AN: 42890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35408

Middle Eastern (MID) AF: 0.000312 AC: 1 AN: 3204

European-Non Finnish (NFE) AF: 0.00000206 AC: 2 AN: 972600

Other (OTH) AF: 0.000484 AC: 23 AN: 47510

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74476

African (AFR) AF: 0.000120 AC: 5 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5168

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000159

Asia WGS AF: 0.00377 AC: 13 AN: 3464

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Junctional epidermolysis bullosa with pyloric atresia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.96
PhyloP100		0.58
PromoterAI		-0.012	Neutral
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

Other links and lift over

dbSNP: rs373890886; hg19: chr2-173292395;