rs377395392

Variant names:

• chr2-165945518-A-G
• rs377395392
• NM_024753.5:c.429+6T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000243344.8(TTC21B):​c.429+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,612,090 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: TTC21B ENST00000243344.8 splice_region, intron
• Scores: Splicing: ADA: 0.01512
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.16
• Publications: 0 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-AS1 (HGNC:41115): (TTC21B antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-165945518-A-G is Benign according to our data. Variant chr2-165945518-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 261783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000243344.8. 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.429+6T>C		splice_region intron	N/A	NP_079029.3
	TTC21B-AS1	NR_038983.1		n.277-1679A>G		intron	N/A
	TTC21B-AS1	NR_038984.1		n.221-1679A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.429+6T>C		splice_region intron	N/A	ENSP00000243344.7
	TTC21B	ENST00000464374.5	TSL:1	n.469+6T>C		splice_region intron	N/A
	TTC21B	ENST00000679840.1		c.429+6T>C		splice_region intron	N/A	ENSP00000505248.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000304 AC: 76 AN: 250112 AF XY: 0.000369

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000475

Gnomad NFE exome AF: 0.000433

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000317 AC: 463 AN: 1459766 Hom.: 2 Cov.: 31 AF XY: 0.000328 AC XY: 238 AN XY: 726304

African (AFR) AF: 0.0000897 AC: 3 AN: 33442

American (AMR) AF: 0.000134 AC: 6 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86218

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52456

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5760

European-Non Finnish (NFE) AF: 0.000331 AC: 368 AN: 1111124

Other (OTH) AF: 0.000414 AC: 25 AN: 60344

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74500

African (AFR) AF: 0.000168 AC: 7 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68018

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

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.000302

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000475

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		3.2
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.27
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: rs377395392; hg19: chr2-166802028;