rs863225150

Variant names:

• chr19-41355008-G-A
• rs863225150
• NM_030578.4:c.220C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_030578.4(B9D2):​c.220C>T​(p.Pro74Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P74P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: B9D2 NM_030578.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.77
• Publications: 3 publications found

Genes affected

B9D2 (HGNC:28636): (B9 domain containing 2) This gene encodes a B9 domain protein, which are exclusively found in ciliated organisms. The gene is upregulated during mucociliary differentiation, and the encoded protein localizes to basal bodies and cilia. Disrupting expression of this gene results in ciliogenesis defects. [provided by RefSeq, Oct 2009]

TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255730 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a chain B9 domain-containing protein 2 (size 174) in uniprot entity B9D2_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_030578.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-41355008-G-A is Pathogenic according to our data. Variant chr19-41355008-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B9D2	NM_030578.4	c.220C>T	p.Pro74Ser	missense_variant	Exon 4 of 4	ENST00000243578.8	NP_085055.2
B9D2	XM_011527349.3	c.220C>T	p.Pro74Ser	missense_variant	Exon 4 of 4		XP_011525651.1
B9D2	XM_011527350.3	c.61C>T	p.Pro21Ser	missense_variant	Exon 3 of 3		XP_011525652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B9D2	ENST00000243578.8	c.220C>T	p.Pro74Ser	missense_variant	Exon 4 of 4	1	NM_030578.4	ENSP00000243578.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome Pathogenic:1

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Joubert syndrome 34 Pathogenic:1

Aug 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Joubert syndrome and related disorders Pathogenic:1

Jun 19, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: B9D2 c.220C>T (p.Pro74Ser) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 214072 control chromosomes. c.220C>T has been reported in the literature in a compound heterozygous individual affected with Joubert Syndrome, who carried the variant c.463G>A (p.Gly155Ser) in trans (Bachmann-Gagescu_2015). A recent publication reported experimental evidence characterizing both variants alone and together in a C. elegans model system, and demonstrated that the cellular level, localization and function were moderately (P74S) or severely (G155S) altered, confirming that both variant alleles are pathogenic in worms, and compound heterozygous worms phenocopy worms homozygous for P74S (Lange_2021). The following publications have been ascertained in the context of this evaluation (PMID: 26092869, 33234550, 28771248, 31411728). ClinVar contains an entry for this variant (Variation ID: 217558). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		8.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.94		Gain of MoRF binding (P = 0.0378);
MVP		0.92
MPC		0.86
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.94
gMVP		0.84
Mutation Taster		=36/64	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs863225150; hg19: chr19-41860913;