2-165911403-C-G

Variant names:

• chr2-165911403-C-G
• rs80225158
• NM_024753.5:c.2385G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_024753.5(TTC21B):​c.2385G>C​(p.Leu795Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,613,778 control chromosomes in the GnomAD database, including 703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L795L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (126 hom., cov: 32)
  • Exomes 𝑓: 0.013 (577 hom.)
• Consequence: TTC21B NM_024753.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.62
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-165911403-C-G is Benign according to our data. Variant chr2-165911403-C-G is described in ClinVar as Benign. ClinVar VariationId is 96138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0987 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	NM_024753.5	MANE Select	c.2385G>C	p.Leu795Leu	synonymous	Exon 18 of 29	NP_079029.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.2385G>C	p.Leu795Leu	synonymous	Exon 18 of 29	ENSP00000243344.7
	TTC21B	ENST00000679840.1		c.2385G>C	p.Leu795Leu	synonymous	Exon 18 of 27	ENSP00000505248.1
	TTC21B	ENST00000679799.1		c.2385G>C	p.Leu795Leu	synonymous	Exon 18 of 28	ENSP00000505208.1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2975 AN: 152064 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0636

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00670

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0297 AC: 7455 AN: 251202 AF XY: 0.0245

Gnomad AFR exome AF: 0.00818

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.0669

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.00642

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0129 AC: 18887 AN: 1461598 Hom.: 577 Cov.: 31 AF XY: 0.0121 AC XY: 8762 AN XY: 727116

African (AFR) AF: 0.00660 AC: 221 AN: 33464

American (AMR) AF: 0.129 AC: 5780 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00410 AC: 107 AN: 26122

East Asian (EAS) AF: 0.0748 AC: 2964 AN: 39618

South Asian (SAS) AF: 0.00332 AC: 286 AN: 86248

European-Finnish (FIN) AF: 0.0223 AC: 1190 AN: 53412

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5758

European-Non Finnish (NFE) AF: 0.00684 AC: 7610 AN: 1111876

Other (OTH) AF: 0.0119 AC: 719 AN: 60380

GnomAD4 genome AF: 0.0195 AC: 2973 AN: 152180 Hom.: 126 Cov.: 32 AF XY: 0.0215 AC XY: 1603 AN XY: 74402

African (AFR) AF: 0.00696 AC: 289 AN: 41526

American (AMR) AF: 0.103 AC: 1572 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.0634 AC: 328 AN: 5174

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4816

European-Finnish (FIN) AF: 0.0241 AC: 255 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00671 AC: 456 AN: 68008

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.00605 Hom.: 3

Bravo AF: 0.0258

Asia WGS AF: 0.0280 AC: 98 AN: 3476

EpiCase AF: 0.00676

EpiControl AF: 0.00587

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Asphyxiating thoracic dystrophy 4 (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Jeune thoracic dystrophy;C0687120:Nephronophthisis (1)
-	-	1	Nephronophthisis 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.7
DANN	Benign	0.86
PhyloP100		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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: rs80225158; hg19: chr2-166767913; COSMIC: COSV99691924; COSMIC: COSV99691924;