8-33496729-T-C

Variant names:

• chr8-33496729-T-C
• rs149061391
• NM_032509.4:c.627T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_032509.4(MAK16):​c.627T>C​(p.Asp209Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,610,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: MAK16 NM_032509.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.33
• Publications: 0 publications found

Genes affected

MAK16 (HGNC:13703): (MAK16 homolog) Enables RNA binding activity. Predicted to be involved in maturation of 5.8S rRNA and maturation of LSU-rRNA. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

TTI2 (HGNC:26262): (TELO2 interacting protein 2) This gene encodes a regulator of the DNA damage response. The protein is a component of the Triple T complex (TTT) which also includes telomere length regulation protein and TELO2 interacting protein 1. The TTT complex is involved in cellular resistance to DNA damage stresses and may act as a regulator of phosphoinositide-3-kinase-related protein kinase (PIKK) abundance. [provided by RefSeq, May 2013]

TTI2 Gene-Disease associations (from GenCC):

• severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-33496729-T-C is Benign according to our data. Variant chr8-33496729-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2658530.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.33 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032509.4. 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
	MAK16	NM_032509.4	MANE Select	c.627T>C	p.Asp209Asp	synonymous	Exon 8 of 10	NP_115898.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAK16	ENST00000360128.11	TSL:1 MANE Select	c.627T>C	p.Asp209Asp	synonymous	Exon 8 of 10	ENSP00000353246.5	Q9BXY0
	MAK16	ENST00000929670.1		c.1005T>C	p.Asp335Asp	synonymous	Exon 8 of 10	ENSP00000599729.1
	MAK16	ENST00000929669.1		c.624T>C	p.Asp208Asp	synonymous	Exon 8 of 10	ENSP00000599728.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152144 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000277 AC: 68 AN: 245654 AF XY: 0.000294

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.000504

Gnomad ASJ exome AF: 0.000303

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1457760 Hom.: 0 Cov.: 29 AF XY: 0.000182 AC XY: 132 AN XY: 725066

African (AFR) AF: 0.000209 AC: 7 AN: 33424

American (AMR) AF: 0.000498 AC: 22 AN: 44202

Ashkenazi Jewish (ASJ) AF: 0.000731 AC: 19 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52954

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5760

European-Non Finnish (NFE) AF: 0.000162 AC: 180 AN: 1109896

Other (OTH) AF: 0.000597 AC: 36 AN: 60260

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152262 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74456

African (AFR) AF: 0.0000241 AC: 1 AN: 41546

American (AMR) AF: 0.000393 AC: 6 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

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

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.000295

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

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	-0.86
CADD	Benign	1.2
DANN	Benign	0.66
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs149061391; hg19: chr8-33354247;