4-103031712-G-C

Position:

• chr4-103031712-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_178833.7(SLC9B2):​c.1243C>G​(p.Pro415Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,611,908 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (40 hom.)
• Consequence: SLC9B2 NM_178833.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.42

Genes affected

SLC9B2 (HGNC:25143): (solute carrier family 9 member B2) Sodium hydrogen antiporters, such as NHEDC2, convert the proton motive force established by the respiratory chain or the F1F0 mitochondrial ATPase into sodium gradients that drive other energy-requiring processes, transduce environmental signals into cell responses, or function in drug efflux (Xiang et al., 2007 [PubMed 18000046]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028415918).
• BP6: Variant 4-103031712-G-C is Benign according to our data. Variant chr4-103031712-G-C is described in ClinVar as [Benign]. Clinvar id is 775219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1596/152178) while in subpopulation AFR AF= 0.0327 (1356/41522). AF 95% confidence interval is 0.0312. There are 19 homozygotes in gnomad4. There are 739 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC9B2	NM_178833.7	c.1243C>G	p.Pro415Ala	missense_variant	10/12	ENST00000394785.9	NP_849155.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC9B2	ENST00000394785.9	c.1243C>G	p.Pro415Ala	missense_variant	10/12	2	NM_178833.7	ENSP00000378265	P1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1589 AN: 152060 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00525

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00369 AC: 924 AN: 250410 Hom.: 11 AF XY: 0.00306 AC XY: 414 AN XY: 135354

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.000996

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.00207

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00219 AC: 3202 AN: 1459730 Hom.: 40 Cov.: 30 AF XY: 0.00216 AC XY: 1565 AN XY: 726204

Gnomad4 AFR exome AF: 0.0324

Gnomad4 AMR exome AF: 0.00317

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.00370

GnomAD4 genome AF: 0.0105 AC: 1596 AN: 152178 Hom.: 19 Cov.: 32 AF XY: 0.00993 AC XY: 739 AN XY: 74412

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.00524

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00297 Hom.: 2

Bravo AF: 0.0122

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0354 AC: 156

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00414 AC: 503

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00213

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.75
DEOGEN2	Benign	0.066	T;.;T;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	.;T;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L;.;.
MutationTaster	Benign	0.95	D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.44	T;T;T;T;T
Sift4G	Benign	0.76	T;T;T;T;T
Polyphen		0.014	B;.;B;B;B
Vest4		0.40
MVP		0.37
MPC		0.020
ClinPred		0.020	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs72943528; hg19: chr4-103952869;