rs142724470

chr6-35951201-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09172115).
• BS2: High AC in GnomAd at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A8	NM_052961.4	c.2434G>A	p.Glu812Lys	missense_variant	19/20	ENST00000490799.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A8	ENST00000490799.6	c.2434G>A	p.Glu812Lys	missense_variant	19/20	1	NM_052961.4	P1

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

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 251460 Hom.: 1 AF XY: 0.000206 AC XY: 28 AN XY: 135906

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 SAS exome AF: 0.000653

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

Gnomad4 AFR exome AF: 0.00314

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000828

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

Gnomad4 AFR AF: 0.00237

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000181 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spermatogenic failure 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 02, 2013

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	M;.;M
MutationTaster	Benign	0.89	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.028	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.98	D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs142724470; hg19: chr6-35918978;