chr17-19343354-A-G

Variant names:

• chr17-19343354-A-G
• rs7212549
• NM_015681.6:c.580T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015681.6(B9D1):​c.580T>C​(p.Leu194Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,614,074 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (205 hom.)
• Consequence: B9D1 NM_015681.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.148
• Publications: 4 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: Genomics England PanelApp, G2P
• Joubert syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-19343354-A-G is Benign according to our data. Variant chr17-19343354-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.148 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	NM_015681.6	MANE Select	c.580T>C	p.Leu194Leu	synonymous	Exon 7 of 7	NP_056496.1
	B9D1	NM_001321214.2		c.*105T>C		3_prime_UTR	Exon 7 of 7	NP_001308143.1
	B9D1	NM_001321215.3		c.*356T>C		3_prime_UTR	Exon 6 of 6	NP_001308144.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	ENST00000261499.11	TSL:1 MANE Select	c.580T>C	p.Leu194Leu	synonymous	Exon 7 of 7	ENSP00000261499.4
	B9D1	ENST00000642870.2		c.220T>C	p.Leu74Leu	synonymous	Exon 7 of 7	ENSP00000496409.2
	B9D1	ENST00000663089.1		c.*356T>C		3_prime_UTR	Exon 7 of 7	ENSP00000499469.1

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2419 AN: 152080 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.0453

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.0660

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0110 AC: 2771 AN: 251414 AF XY: 0.0124

Gnomad AFR exome AF: 0.0449

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0143

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00504 AC: 7365 AN: 1461876 Hom.: 205 Cov.: 29 AF XY: 0.00632 AC XY: 4598 AN XY: 727246

African (AFR) AF: 0.0464 AC: 1555 AN: 33480

American (AMR) AF: 0.00324 AC: 145 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0133 AC: 528 AN: 39700

South Asian (SAS) AF: 0.0525 AC: 4532 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1112000

Other (OTH) AF: 0.00773 AC: 467 AN: 60396

GnomAD4 genome AF: 0.0159 AC: 2422 AN: 152198 Hom.: 41 Cov.: 33 AF XY: 0.0169 AC XY: 1255 AN XY: 74418

African (AFR) AF: 0.0453 AC: 1881 AN: 41514

American (AMR) AF: 0.00772 AC: 118 AN: 15292

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

East Asian (EAS) AF: 0.0137 AC: 71 AN: 5178

South Asian (SAS) AF: 0.0658 AC: 317 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68000

Other (OTH) AF: 0.0114 AC: 24 AN: 2104

Alfa AF: 0.00573 Hom.: 29

Bravo AF: 0.0162

Asia WGS AF: 0.0320 AC: 111 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Meckel syndrome, type 9 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.37
DANN	Benign	0.55
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

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: rs7212549; hg19: chr17-19246667;