NM_000441.2:c.2291C>A

Variant names:

• chr7-107712594-C-A
• NM_000441.2:c.2291C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000441.2(SLC26A4):​c.2291C>A​(p.Thr764Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,433,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.158

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 272) in uniprot entity S26A4_HUMAN there are 26 pathogenic changes around while only 8 benign (76%) in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06299347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.2291C>A	p.Thr764Lys	missense_variant	Exon 20 of 21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2291C>A	p.Thr764Lys	missense_variant	Exon 20 of 21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000492030.2	n.477C>A		non_coding_transcript_exon_variant	Exon 5 of 6	5
SLC26A4	ENST00000644846.1	n.*193C>A		non_coding_transcript_exon_variant	Exon 9 of 10			ENSP00000494344.1
SLC26A4	ENST00000644846.1	n.*193C>A		3_prime_UTR_variant	Exon 9 of 10			ENSP00000494344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1433584 Hom.: 0 Cov.: 26 AF XY: 0.00000140 AC XY: 1 AN XY: 714986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.69
DANN	Benign	0.71
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.48	.;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.040	N;.
REVEL	Benign	0.25
Sift	Benign	0.74	T;.
Sift4G	Benign	0.93	T;.
Polyphen		0.049	B;B
Vest4		0.30
MutPred		0.30		Gain of ubiquitination at T764 (P = 0.0029);Gain of ubiquitination at T764 (P = 0.0029);
MVP		0.70
MPC		0.011
ClinPred		0.038	T
GERP RS		-7.2
Varity_R		0.036
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-107353039;