17-19343326-G-A

Variant names:

• chr17-19343326-G-A
• rs1399095814
• NM_015681.6:c.608C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015681.6(B9D1):​c.608C>T​(p.Pro203Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: B9D1 NM_015681.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 0 publications found

Genes affected

B9D1 (HGNC:24123): (B9 domain containing 1) This gene encodes a B9 domain-containing protein, one of several that are involved in ciliogenesis. Alterations in expression of this gene have been found in a family with Meckel syndrome. Meckel syndrome has been associated with at least six different genes. This gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Mar 2016]

B9D1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 27

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Meckel syndrome, type 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0682978).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015681.6. 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
	B9D1	NM_015681.6	MANE Select	c.608C>T	p.Pro203Leu	missense	Exon 7 of 7	NP_056496.1	Q9UPM9-1
	B9D1	NM_001321214.2		c.*133C>T		3_prime_UTR	Exon 7 of 7	NP_001308143.1	A8MYG7
	B9D1	NM_001321215.3		c.*384C>T		3_prime_UTR	Exon 6 of 6	NP_001308144.1	A0A2R8Y646

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	ENST00000261499.11	TSL:1 MANE Select	c.608C>T	p.Pro203Leu	missense	Exon 7 of 7	ENSP00000261499.4	Q9UPM9-1
	B9D1	ENST00000642870.2		c.248C>T	p.Pro83Leu	missense	Exon 7 of 7	ENSP00000496409.2	A0A2R8Y822
	B9D1	ENST00000663089.1		c.*384C>T		3_prime_UTR	Exon 7 of 7	ENSP00000499469.1	A0A590UJK9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.29	N
PhyloP100		1.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.17
MutPred		0.25		Loss of glycosylation at P203 (P = 0.0384)
MVP		0.30
MPC		0.79
ClinPred		0.38	T
GERP RS		2.0
Varity_R		0.048
gMVP		0.26
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1399095814; hg19: chr17-19246639;