rs73969727

Variant names:

• chr2-165913561-T-C
• rs73969727
• NM_024753.5:c.2211+13A>G

Variant summary

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

The NM_024753.5(TTC21B):​c.2211+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00705 in 1,585,854 control chromosomes in the GnomAD database, including 644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (340 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (304 hom.)
• Consequence: TTC21B NM_024753.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.251
• Publications: 4 publications found

Genes affected

TTC21B (HGNC:25660): (tetratricopeptide repeat domain 21B) This gene encodes a member of TTC21 family, containing several tetratricopeptide repeat (TPR) domains. This protein is localized to the cilium axoneme, and may play a role in retrograde intraflagellar transport in cilia. Mutations in this gene are associated with various ciliopathies, nephronophthisis 12, and asphyxiating thoracic dystrophy 4. [provided by RefSeq, Oct 2011]

TTC21B Gene-Disease associations (from GenCC):

• nephronophthisis 12

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• asphyxiating thoracic dystrophy 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-165913561-T-C is Benign according to our data. Variant chr2-165913561-T-C is described in ClinVar as Benign. ClinVar VariationId is 261773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024753.5. 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
	TTC21B	NM_024753.5	MANE Select	c.2211+13A>G		intron	N/A	NP_079029.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.2211+13A>G		intron	N/A	ENSP00000243344.7
	TTC21B	ENST00000679840.1		c.2211+13A>G		intron	N/A	ENSP00000505248.1
	TTC21B	ENST00000679799.1		c.2211+13A>G		intron	N/A	ENSP00000505208.1

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 5714 AN: 152082 Hom.: 339 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.00964 AC: 2402 AN: 249180 AF XY: 0.00686

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.00599

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000356

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00381 AC: 5465 AN: 1433654 Hom.: 304 Cov.: 26 AF XY: 0.00327 AC XY: 2340 AN XY: 715010

African (AFR) AF: 0.131 AC: 4310 AN: 32824

American (AMR) AF: 0.00757 AC: 338 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.000187 AC: 16 AN: 85488

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53210

Middle Eastern (MID) AF: 0.00929 AC: 53 AN: 5708

European-Non Finnish (NFE) AF: 0.000193 AC: 210 AN: 1086900

Other (OTH) AF: 0.00903 AC: 537 AN: 59458

GnomAD4 genome AF: 0.0376 AC: 5721 AN: 152200 Hom.: 340 Cov.: 32 AF XY: 0.0364 AC XY: 2706 AN XY: 74404

African (AFR) AF: 0.130 AC: 5413 AN: 41496

American (AMR) AF: 0.0145 AC: 221 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68018

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0196 Hom.: 53

Bravo AF: 0.0432

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Asphyxiating thoracic dystrophy 4 (1)
-	-	1	Jeune thoracic dystrophy;C0687120:Nephronophthisis (1)
-	-	1	Nephronophthisis 12 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.9
DANN	Benign	0.68
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs73969727; hg19: chr2-166770071;