6-30721970-A-G

Variant names:

• chr6-30721970-A-G
• rs369813241
• NM_178014.4:c.58-567A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001293212.2(TUBB):​c.92A>G​(p.His31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 865,360 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (1 hom.)
• Consequence: TUBB NM_001293212.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.388
• Publications: 0 publications found

Genes affected

TUBB (HGNC:20778): (tubulin beta class I) This gene encodes a beta tubulin protein. This protein forms a dimer with alpha tubulin and acts as a structural component of microtubules. Mutations in this gene cause cortical dysplasia, complex, with other brain malformations 6. Alternative splicing results in multiple splice variants. There are multiple pseudogenes for this gene on chromosomes 1, 6, 7, 8, 9, and 13. [provided by RefSeq, Jun 2014]

TUBB Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations 6

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• multiple benign circumferential skin creases on limbs 1

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• TUBB3-related tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• multiple benign circumferential skin creases on limbs

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP2: Missense variant in the TUBB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 5.6252 (above the threshold of 3.09). Trascript score misZ: 8.0682 (above the threshold of 3.09). GenCC associations: The gene is linked to TUBB3-related tubulinopathy, multiple benign circumferential skin creases on limbs 1, complex cortical dysplasia with other brain malformations 6, multiple benign circumferential skin creases on limbs.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-30721970-A-G is Benign according to our data. Variant chr6-30721970-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3052561.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001293212.2. 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
	TUBB	NM_178014.4	MANE Select	c.58-567A>G		intron	N/A	NP_821133.1	Q5SU16
	TUBB	NM_001293212.2		c.92A>G	p.His31Arg	missense	Exon 1 of 4	NP_001280141.1
	TUBB	NM_001293214.2		c.35-948A>G		intron	N/A	NP_001280143.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB	ENST00000327892.13	TSL:1 MANE Select	c.58-567A>G		intron	N/A	ENSP00000339001.7	P07437
	TUBB	ENST00000396389.5	TSL:5	c.-290A>G		5_prime_UTR	Exon 1 of 4	ENSP00000379672.1	Q5JP53
	TUBB	ENST00000396384.1	TSL:3	c.-404A>G		5_prime_UTR	Exon 1 of 4	ENSP00000379668.1	Q5ST81

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.0000883 AC: 63 AN: 713218 Hom.: 1 Cov.: 9 AF XY: 0.0000513 AC XY: 17 AN XY: 331600

African (AFR) AF: 0.00 AC: 0 AN: 13480

American (AMR) AF: 0.00 AC: 0 AN: 1216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4418

East Asian (EAS) AF: 0.00328 AC: 10 AN: 3052

South Asian (SAS) AF: 0.000742 AC: 11 AN: 14834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1386

European-Non Finnish (NFE) AF: 0.00000461 AC: 3 AN: 651248

Other (OTH) AF: 0.00167 AC: 39 AN: 23342

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152142 Hom.: 2 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74390

African (AFR) AF: 0.00 AC: 0 AN: 41502

American (AMR) AF: 0.000196 AC: 3 AN: 15290

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

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67968

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

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000162

Asia WGS AF: 0.0240 AC: 82 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TUBB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.8
DANN	Benign	0.23
PhyloP100		-0.39
PromoterAI		-0.0090	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369813241; hg19: chr6-30689747;