9-98784057-C-T

Variant names:

• chr9-98784057-C-T
• rs373872443
• NM_173551.5:c.1008G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_173551.5(ANKS6):​c.1008G>A​(p.Thr336Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,611,234 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00064 (4 hom.)
• Consequence: ANKS6 NM_173551.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0490
• Publications: 0 publications found

Genes affected

ANKS6 (HGNC:26724): (ankyrin repeat and sterile alpha motif domain containing 6) This gene encodes a protein containing multiple ankyrin repeats and a SAM domain. It is thought that this protein may localize to the proximal region of the primary cilium, and may play a role in renal and cardiovascular development. Mutations in this gene have been shown to cause a form of nephronophthisis (NPHP16), a chronic tubulo-interstitial nephritis. [provided by RefSeq, Jul 2015]

ANKS6 Gene-Disease associations (from GenCC):

• nephronophthisis 16

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 9-98784057-C-T is Benign according to our data. Variant chr9-98784057-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 541406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.049 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173551.5. 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
	ANKS6	NM_173551.5	MANE Select	c.1008G>A	p.Thr336Thr	synonymous	Exon 4 of 15	NP_775822.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKS6	ENST00000353234.5	TSL:1 MANE Select	c.1008G>A	p.Thr336Thr	synonymous	Exon 4 of 15	ENSP00000297837.6
	ANKS6	ENST00000941017.1		c.1008G>A	p.Thr336Thr	synonymous	Exon 4 of 13	ENSP00000611076.1
	ANKS6	ENST00000927508.1		c.1008G>A	p.Thr336Thr	synonymous	Exon 4 of 13	ENSP00000597567.1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152172 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00108 AC: 267 AN: 246350 AF XY: 0.00112

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.000842

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000559

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.000640 AC: 933 AN: 1458944 Hom.: 4 Cov.: 31 AF XY: 0.000664 AC XY: 482 AN XY: 725522

African (AFR) AF: 0.00165 AC: 55 AN: 33406

American (AMR) AF: 0.000971 AC: 43 AN: 44294

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 372 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.0000820 AC: 7 AN: 85402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5682

European-Non Finnish (NFE) AF: 0.000322 AC: 358 AN: 1110844

Other (OTH) AF: 0.00158 AC: 95 AN: 60304

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152290 Hom.: 0 Cov.: 31 AF XY: 0.000994 AC XY: 74 AN XY: 74462

African (AFR) AF: 0.00152 AC: 63 AN: 41560

American (AMR) AF: 0.000981 AC: 15 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00195 Hom.: 2

Bravo AF: 0.00120

EpiCase AF: 0.000933

EpiControl AF: 0.000777

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Nephronophthisis 16 (2)
-	-	1	ANKS6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	5.5
DANN	Benign	0.80
PhyloP100		0.049
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs373872443; hg19: chr9-101546339; COSMIC: COSV108197466;