rs2234319

Variant names:

• chr22-18110361-C-T
• rs2234319
• ENST00000474897.6:n.815-11118C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000474897.6(ENSG00000288683):​n.815-11118C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00555 in 218,378 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: ENSG00000288683 ENST00000474897.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.85
• Publications: 0 publications found

Genes affected

ENSG00000288683 (HGNC:):

TUBA8 (HGNC:12410): (tubulin alpha 8) This gene encodes a member of the alpha tubulin protein family. Alpha tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene are associated with polymicrogyria and optic nerve hypoplasia. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

TUBA8 Gene-Disease associations (from GenCC):

• polymicrogyria with optic nerve hypoplasia

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-18110361-C-T is Benign according to our data. Variant chr22-18110361-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1198833.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00783 (1192/152320) while in subpopulation AFR AF = 0.0272 (1132/41574). AF 95% confidence interval is 0.0259. There are 10 homozygotes in GnomAd4. There are 580 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000474897.6. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000288683	ENST00000474897.6	TSL:5	n.815-11118C>T		intron	N/A	ENSP00000434235.2	E9PRC5
	TUBA8	ENST00000901605.1		c.-505C>T		5_prime_UTR	Exon 1 of 5	ENSP00000571664.1
	TUBA8	ENST00000680175.1		c.-505C>T		5_prime_UTR	Exon 1 of 6	ENSP00000505461.1	A0A7P0T945

Frequencies

GnomAD3 genomes AF: 0.00779 AC: 1186 AN: 152202 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.000318 AC: 21 AN: 66058 Hom.: 0 Cov.: 0 AF XY: 0.000375 AC XY: 13 AN XY: 34624

African (AFR) AF: 0.0198 AC: 8 AN: 404

American (AMR) AF: 0.00145 AC: 2 AN: 1380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1514

East Asian (EAS) AF: 0.00 AC: 0 AN: 934

South Asian (SAS) AF: 0.0000902 AC: 1 AN: 11086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000119 AC: 5 AN: 42084

Other (OTH) AF: 0.00126 AC: 5 AN: 3958

GnomAD4 genome AF: 0.00783 AC: 1192 AN: 152320 Hom.: 10 Cov.: 32 AF XY: 0.00779 AC XY: 580 AN XY: 74480

African (AFR) AF: 0.0272 AC: 1132 AN: 41574

American (AMR) AF: 0.00255 AC: 39 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68032

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00569 Hom.: 0

Bravo AF: 0.00855

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.58
DANN	Benign	0.89
PhyloP100		-1.8
PromoterAI		-0.015	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2234319; hg19: chr22-18593127;