rs142724470

Variant names:

• chr6-35951201-C-T
• rs142724470
• NM_052961.4:c.2434G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_052961.4(SLC26A8):​c.2434G>A​(p.Glu812Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,613,242 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00069 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: SLC26A8 NM_052961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 2.60
• Publications: 5 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)

ENSG00000304790 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09172115).
• BP6: Variant 6-35951201-C-T is Benign according to our data. Variant chr6-35951201-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 50910.

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.2434G>A	p.Glu812Lys	missense	Exon 19 of 20	NP_443193.1	Q96RN1-1
	SLC26A8	NM_001193476.2		c.2434G>A	p.Glu812Lys	missense	Exon 19 of 20	NP_001180405.1	Q96RN1-1
	SLC26A8	NM_138718.3		c.2119G>A	p.Glu707Lys	missense	Exon 17 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.2434G>A	p.Glu812Lys	missense	Exon 19 of 20	ENSP00000417638.1	Q96RN1-1
	SLC26A8	ENST00000394602.6	TSL:1	c.2119G>A	p.Glu707Lys	missense	Exon 17 of 18	ENSP00000378100.2	Q96RN1-2
	SLC26A8	ENST00000355574.6	TSL:2	c.2434G>A	p.Glu812Lys	missense	Exon 19 of 20	ENSP00000347778.2	Q96RN1-1

Frequencies

GnomAD3 genomes AF: 0.000687 AC: 104 AN: 151438 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000966

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251460 AF XY: 0.000206

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000120 AC: 176 AN: 1461688 Hom.: 1 Cov.: 35 AF XY: 0.000131 AC XY: 95 AN XY: 727164

African (AFR) AF: 0.00314 AC: 105 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000533 AC: 46 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111910

Other (OTH) AF: 0.0000828 AC: 5 AN: 60378

GnomAD4 genome AF: 0.000686 AC: 104 AN: 151554 Hom.: 1 Cov.: 31 AF XY: 0.000635 AC XY: 47 AN XY: 73998

African (AFR) AF: 0.00237 AC: 98 AN: 41280

American (AMR) AF: 0.00 AC: 0 AN: 15158

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67978

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.000744

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)
1	-	-	Spermatogenic failure 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.093	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.092	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.021	D
Polyphen		0.98	D
Vest4		0.80
MVP		0.79
MPC		0.75
ClinPred		0.065	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.67
Mutation Taster		=88/12	disease causing (ClinVar)

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: rs142724470; hg19: chr6-35918978;