2-32532171-G-GTGTGTGTGTGT

Variant names:

• chr2-32532171-G-GTGTGTGTGTGT
• rs35999329
• NM_016252.4:c.12291+620_12291+621insTGTGTGTGTGT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_016252.4(BIRC6):​c.12291+620_12291+621insTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0076 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BIRC6 NM_016252.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.931
• Publications: 2 publications found

Genes affected

BIRC6 (HGNC:13516): (baculoviral IAP repeat containing 6) This gene encodes a protein with a BIR (baculoviral inhibition of apoptosis protein repeat) domain and a UBCc (ubiquitin-conjugating enzyme E2, catalytic) domain. This protein inhibits apoptosis by facilitating the degradation of apoptotic proteins by ubiquitination. [provided by RefSeq, Jul 2008]

MIR558 (HGNC:32814): (microRNA 558) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016252.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIRC6	NM_016252.4	MANE Select	c.12291+620_12291+621insTGTGTGTGTGT		intron	N/A	NP_057336.3
	MIR558	NR_030285.1		n.19_20insTGTGTGTGTGT		non_coding_transcript_exon	Exon 1 of 1
	BIRC6	NM_001378125.1		c.12288+620_12288+621insTGTGTGTGTGT		intron	N/A	NP_001365054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIRC6	ENST00000421745.7	TSL:1 MANE Select	c.12291+620_12291+621insTGTGTGTGTGT		intron	N/A	ENSP00000393596.2
	MIR558	ENST00000384920.1	TSL:6	n.19_20insTGTGTGTGTGT		non_coding_transcript_exon	Exon 1 of 1
	BIRC6	ENST00000700518.1		c.12240+620_12240+621insTGTGTGTGTGT		intron	N/A	ENSP00000515025.1

Frequencies

GnomAD3 genomes AF: 0.000569 AC: 85 AN: 149286 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000617

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.000600

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000793

Gnomad SAS AF: 0.000643

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000625

Gnomad OTH AF: 0.000487

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00764 AC: 2868 AN: 375564 Hom.: 0 Cov.: 0 AF XY: 0.00776 AC XY: 1661 AN XY: 214070

African (AFR) AF: 0.00899 AC: 92 AN: 10232

American (AMR) AF: 0.0102 AC: 362 AN: 35650

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 176 AN: 11510

East Asian (EAS) AF: 0.00307 AC: 40 AN: 13026

South Asian (SAS) AF: 0.00850 AC: 560 AN: 65912

European-Finnish (FIN) AF: 0.0106 AC: 335 AN: 31570

Middle Eastern (MID) AF: 0.0116 AC: 15 AN: 1292

European-Non Finnish (NFE) AF: 0.00627 AC: 1192 AN: 190014

Other (OTH) AF: 0.00587 AC: 96 AN: 16358

GnomAD4 genome AF: 0.000582 AC: 87 AN: 149402 Hom.: 0 Cov.: 0 AF XY: 0.000672 AC XY: 49 AN XY: 72900

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000640 AC: 26 AN: 40624

American (AMR) AF: 0.000666 AC: 10 AN: 15016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.000795 AC: 4 AN: 5032

South Asian (SAS) AF: 0.000644 AC: 3 AN: 4660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000625 AC: 42 AN: 67204

Other (OTH) AF: 0.000482 AC: 1 AN: 2074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000167254), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0158 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35999329; hg19: chr2-32757238;