chr2-165929290-G-C

Variant names:

• chr2-165929290-G-C
• rs185089786
• NM_024753.5:c.1231C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024753.5(TTC21B):​c.1231C>G​(p.Arg411Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,612,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.521
• Publications: 9 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):

• asphyxiating thoracic dystrophy 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nephronophthisis 12

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.077646285).

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.1231C>G	p.Arg411Gly	missense	Exon 11 of 29	NP_079029.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.1231C>G	p.Arg411Gly	missense	Exon 11 of 29	ENSP00000243344.7	Q7Z4L5-1
	TTC21B	ENST00000464374.5	TSL:1	n.1271C>G		non_coding_transcript_exon	Exon 11 of 11
	TTC21B	ENST00000679840.1		c.1231C>G	p.Arg411Gly	missense	Exon 11 of 27	ENSP00000505248.1	A0A7P0T8P4

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 250066 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000110 AC: 160 AN: 1459924 Hom.: 0 Cov.: 31 AF XY: 0.0000964 AC XY: 70 AN XY: 726322

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.000202 AC: 9 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53354

Middle Eastern (MID) AF: 0.000529 AC: 3 AN: 5666

European-Non Finnish (NFE) AF: 0.000122 AC: 135 AN: 1110816

Other (OTH) AF: 0.000199 AC: 12 AN: 60298

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67912

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.0000546

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Asphyxiating thoracic dystrophy 4;C3151186:Nephronophthisis 12 (1)
-	1	-	Jeune thoracic dystrophy;C0687120:Nephronophthisis (1)
-	1	-	not provided (1)
-	1	-	TTC21B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.33	N
PhyloP100		0.52
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.73	N
REVEL	Benign	0.22
Sift	Benign	0.45	T
Sift4G	Benign	0.42	T
Polyphen		0.0010	B
Vest4		0.71
MVP		0.072
MPC		0.035
ClinPred		0.014	T
GERP RS		-0.10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.29
Mutation Taster		=34/66	disease causing

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: rs185089786; hg19: chr2-166785800;