19-41354785-C-G

Variant names:

• chr19-41354785-C-G
• rs149500212
• NM_030578.4:c.443G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_030578.4(B9D2):​c.443G>C​(p.Arg148Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R148H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: B9D2 NM_030578.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.06
• Publications: 0 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: Likely_pathogenic. The variant received 6 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, 0.882

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030578.4. 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
	B9D2	NM_030578.4	MANE Select	c.443G>C	p.Arg148Pro	missense	Exon 4 of 4	NP_085055.2	Q9BPU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D2	ENST00000243578.8	TSL:1 MANE Select	c.443G>C	p.Arg148Pro	missense	Exon 4 of 4	ENSP00000243578.2	Q9BPU9
	TMEM91	ENST00000539627.5	TSL:1	c.-30+3583C>G		intron	N/A	ENSP00000441900.1	F5GWC9
	B9D2	ENST00000675972.1		c.443G>C	p.Arg148Pro	missense	Exon 4 of 4	ENSP00000501911.1	Q9BPU9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461666 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.027	D
Polyphen		0.99	D
Vest4		0.87
MutPred		0.60		Loss of catalytic residue at R148 (P = 0.0018)
MVP		0.74
MPC		0.99
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.82
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149500212; hg19: chr19-41860690;