22-18130836-C-T

Variant names:

• chr22-18130836-C-T
• rs2234338
• NM_018943.3:c.1057-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018943.3(TUBA8):​c.1057-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,613,396 control chromosomes in the GnomAD database, including 1,418 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (593 hom., cov: 32)
  • Exomes 𝑓: 0.022 (825 hom.)
• Consequence: TUBA8 NM_018943.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003785
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.422
• Publications: 6 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: Unknown, AR Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ENSG00000288683 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 22-18130836-C-T is Benign according to our data. Variant chr22-18130836-C-T is described in ClinVar as Benign. ClinVar VariationId is 137853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA8	NM_018943.3	MANE Select	c.1057-7C>T		splice_region intron	N/A	NP_061816.1
	TUBA8	NM_001193414.2		c.859-7C>T		splice_region intron	N/A	NP_001180343.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA8	ENST00000330423.8	TSL:1 MANE Select	c.1057-7C>T		splice_region intron	N/A	ENSP00000333326.3
	TUBA8	ENST00000416740.2	TSL:1	c.859-7C>T		splice_region intron	N/A	ENSP00000412646.2
	ENSG00000288683	ENST00000474897.6	TSL:5	n.*947-7C>T		splice_region intron	N/A	ENSP00000434235.2

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8931 AN: 152074 Hom.: 590 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.0434

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0425

GnomAD2 exomes AF: 0.0264 AC: 6605 AN: 249958 AF XY: 0.0240

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.00808

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0216 AC: 31550 AN: 1461204 Hom.: 825 Cov.: 31 AF XY: 0.0208 AC XY: 15107 AN XY: 726924

African (AFR) AF: 0.169 AC: 5660 AN: 33452

American (AMR) AF: 0.0168 AC: 751 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00792 AC: 207 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0108 AC: 928 AN: 86236

European-Finnish (FIN) AF: 0.0393 AC: 2099 AN: 53384

Middle Eastern (MID) AF: 0.0173 AC: 92 AN: 5330

European-Non Finnish (NFE) AF: 0.0183 AC: 20303 AN: 1111916

Other (OTH) AF: 0.0250 AC: 1506 AN: 60340

GnomAD4 genome AF: 0.0588 AC: 8951 AN: 152192 Hom.: 593 Cov.: 32 AF XY: 0.0573 AC XY: 4267 AN XY: 74420

African (AFR) AF: 0.163 AC: 6770 AN: 41500

American (AMR) AF: 0.0216 AC: 331 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00871 AC: 42 AN: 4822

European-Finnish (FIN) AF: 0.0434 AC: 460 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0176 AC: 1195 AN: 68000

Other (OTH) AF: 0.0421 AC: 89 AN: 2114

Alfa AF: 0.0331 Hom.: 205

Bravo AF: 0.0614

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0185

EpiControl AF: 0.0171

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	TUBA8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.014
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: rs2234338; hg19: chr22-18613603;