6-36012301-C-T

Variant names:

• chr6-36012301-C-T
• rs140210148
• NM_052961.4:c.260G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_052961.4(SLC26A8):​c.260G>A​(p.Arg87Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,612,042 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (1 hom.)
• Consequence: SLC26A8 NM_052961.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.15
• Publications: 9 publications found

Genes affected

SLC26A8 (HGNC:14468): (solute carrier family 26 member 8) This gene encodes a member of the SLC26 gene family of anion transporters. Family members are well conserved in gene structure and protein length yet have markedly different tissue expression patterns. The expression of this gene appears to be restricted to spermatocytes. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Jul 2010]

SLC26A8 Gene-Disease associations (from GenCC):

• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
• spermatogenic failure 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

LOC105375034 (HGNC:):

ACMG classification

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

• PP5: Variant 6-36012301-C-T is Pathogenic according to our data. Variant chr6-36012301-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 50909.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21989736). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052961.4. 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
	SLC26A8	NM_052961.4	MANE Select	c.260G>A	p.Arg87Gln	missense	Exon 3 of 20	NP_443193.1	Q96RN1-1
	SLC26A8	NM_001193476.2		c.260G>A	p.Arg87Gln	missense	Exon 3 of 20	NP_001180405.1	Q96RN1-1
	SLC26A8	NM_138718.3		c.260G>A	p.Arg87Gln	missense	Exon 3 of 18	NP_619732.2	Q96RN1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A8	ENST00000490799.6	TSL:1 MANE Select	c.260G>A	p.Arg87Gln	missense	Exon 3 of 20	ENSP00000417638.1	Q96RN1-1
	SLC26A8	ENST00000394602.6	TSL:1	c.260G>A	p.Arg87Gln	missense	Exon 3 of 18	ENSP00000378100.2	Q96RN1-2
	SLC26A8	ENST00000355574.6	TSL:2	c.260G>A	p.Arg87Gln	missense	Exon 3 of 20	ENSP00000347778.2	Q96RN1-1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000309 AC: 77 AN: 249036 AF XY: 0.000319

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000448

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000424

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000732 AC: 1069 AN: 1459780 Hom.: 1 Cov.: 30 AF XY: 0.000680 AC XY: 494 AN XY: 726264

African (AFR) AF: 0.0000600 AC: 2 AN: 33316

American (AMR) AF: 0.000363 AC: 16 AN: 44028

Ashkenazi Jewish (ASJ) AF: 0.000690 AC: 18 AN: 26076

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39636

South Asian (SAS) AF: 0.000175 AC: 15 AN: 85930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000886 AC: 985 AN: 1111322

Other (OTH) AF: 0.000514 AC: 31 AN: 60302

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74442

African (AFR) AF: 0.0000963 AC: 4 AN: 41550

American (AMR) AF: 0.000196 AC: 3 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000495 Hom.: 1

Bravo AF: 0.000344

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000491

EpiControl AF: 0.000890

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Spermatogenic failure 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0024	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.53
Sift	Benign	0.17	T
Sift4G	Benign	0.16	T
Polyphen		0.92	P
Vest4		0.21
MVP		0.74
MPC		0.70
ClinPred		0.073	T
GERP RS		4.8
Varity_R		0.22
gMVP		0.53
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140210148; hg19: chr6-35980078;