22-18121367-C-T

Variant names:

• chr22-18121367-C-T
• rs2234323
• NM_018943.3:c.4-112C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_018943.3(TUBA8):​c.4-112C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 928,756 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.013 (89 hom.)
• Consequence: TUBA8 NM_018943.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0230
• Publications: 0 publications found

Genes affected

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)

ENSG00000288683 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 22-18121367-C-T is Benign according to our data. Variant chr22-18121367-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1205249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1695/152320) while in subpopulation NFE AF = 0.018 (1227/68020). AF 95% confidence interval is 0.0172. There are 17 homozygotes in GnomAd4. There are 821 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018943.3. 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
	TUBA8	NM_018943.3	MANE Select	c.4-112C>T		intron	N/A	NP_061816.1	Q9NY65-1
	TUBA8	NM_001193414.2		c.-195-112C>T		intron	N/A	NP_001180343.1	Q9NY65-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA8	ENST00000330423.8	TSL:1 MANE Select	c.4-112C>T		intron	N/A	ENSP00000333326.3	Q9NY65-1
	TUBA8	ENST00000416740.2	TSL:1	c.-195-112C>T		intron	N/A	ENSP00000412646.2	Q9NY65-2
	ENSG00000288683	ENST00000474897.6	TSL:5	n.815-112C>T		intron	N/A	ENSP00000434235.2	E9PRC5

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1695 AN: 152202 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.0105 AC: 2123 AN: 202232 AF XY: 0.0106

Gnomad AFR exome AF: 0.00319

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.00233

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0191

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.0135 AC: 10462 AN: 776436 Hom.: 89 Cov.: 10 AF XY: 0.0129 AC XY: 5235 AN XY: 407368

African (AFR) AF: 0.00269 AC: 55 AN: 20442

American (AMR) AF: 0.00367 AC: 146 AN: 39754

Ashkenazi Jewish (ASJ) AF: 0.00163 AC: 33 AN: 20188

East Asian (EAS) AF: 0.00 AC: 0 AN: 35766

South Asian (SAS) AF: 0.00249 AC: 169 AN: 67932

European-Finnish (FIN) AF: 0.0196 AC: 987 AN: 50434

Middle Eastern (MID) AF: 0.00364 AC: 16 AN: 4390

European-Non Finnish (NFE) AF: 0.0172 AC: 8586 AN: 499928

Other (OTH) AF: 0.0125 AC: 470 AN: 37602

GnomAD4 genome AF: 0.0111 AC: 1695 AN: 152320 Hom.: 17 Cov.: 32 AF XY: 0.0110 AC XY: 821 AN XY: 74480

African (AFR) AF: 0.00382 AC: 159 AN: 41584

American (AMR) AF: 0.00582 AC: 89 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1227 AN: 68020

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

Alfa AF: 0.0131 Hom.: 2

Bravo AF: 0.00980

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.50
PhyloP100		0.023
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.61		Position offset: -2

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

Other links and lift over

dbSNP: rs2234323; hg19: chr22-18604134;