rs2285643

Variant names:

• chr17-44253099-C-T
• rs2285643
• NM_000342.4:c.2311+19G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-44253099-C-T
• chr17-44253099-C-A
• chr17-44253099-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000342.4(SLC4A1):​c.2311+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00639 in 1,606,888 control chromosomes in the GnomAD database, including 782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (109 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (673 hom.)
• Consequence: SLC4A1 NM_000342.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.62
• Publications: 4 publications found

Genes affected

SLC4A1 (HGNC:11027): (solute carrier family 4 member 1 (Diego blood group)) The protein encoded by this gene is part of the anion exchanger (AE) family and is expressed in the erythrocyte plasma membrane, where it functions as a chloride/bicarbonate exchanger involved in carbon dioxide transport from tissues to lungs. The protein comprises two domains that are structurally and functionally distinct. The N-terminal 40kDa domain is located in the cytoplasm and acts as an attachment site for the red cell skeleton by binding ankyrin. The glycosylated C-terminal membrane-associated domain contains 12-14 membrane spanning segments and carries out the stilbene disulphonate-sensitive exchange transport of anions. The cytoplasmic tail at the extreme C-terminus of the membrane domain binds carbonic anhydrase II. The encoded protein associates with the red cell membrane protein glycophorin A and this association promotes the correct folding and translocation of the exchanger. This protein is predominantly dimeric but forms tetramers in the presence of ankyrin. Many mutations in this gene are known in man, and these mutations can lead to two types of disease: destabilization of red cell membrane leading to hereditary spherocytosis, and defective kidney acid secretion leading to distal renal tubular acidosis. Other mutations that do not give rise to disease result in novel blood group antigens, which form the Diego blood group system. Southeast Asian ovalocytosis (SAO, Melanesian ovalocytosis) results from the heterozygous presence of a deletion in the encoded protein and is common in areas where Plasmodium falciparum malaria is endemic. One null mutation in this gene is known, resulting in very severe anemia and nephrocalcinosis. [provided by RefSeq, Jul 2008]

SLC4A1 Gene-Disease associations (from GenCC):

• autosomal dominant distal renal tubular acidosis

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• cryohydrocytosis

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hereditary spherocytosis type 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• southeast Asian ovalocytosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• renal tubular acidosis, distal, 4, with hemolytic anemia

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-44253099-C-T is Benign according to our data. Variant chr17-44253099-C-T is described in ClinVar as Benign. ClinVar VariationId is 255910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000342.4. 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
	SLC4A1	NM_000342.4	MANE Select	c.2311+19G>A		intron	N/A	NP_000333.1	P02730-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A1	ENST00000262418.12	TSL:1 MANE Select	c.2311+19G>A		intron	N/A	ENSP00000262418.6	P02730-1
	SLC4A1	ENST00000399246.3	TSL:5	c.1213+19G>A		intron	N/A	ENSP00000382190.3	A0A0A0MS98

Frequencies

GnomAD3 genomes AF: 0.00888 AC: 1351 AN: 152142 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0159 AC: 3876 AN: 243402 AF XY: 0.0145

Gnomad AFR exome AF: 0.00424

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.195

Gnomad FIN exome AF: 0.000178

Gnomad NFE exome AF: 0.000694

Gnomad OTH exome AF: 0.00659

GnomAD4 exome AF: 0.00613 AC: 8914 AN: 1454628 Hom.: 673 Cov.: 32 AF XY: 0.00606 AC XY: 4386 AN XY: 723832

African (AFR) AF: 0.00388 AC: 130 AN: 33476

American (AMR) AF: 0.000447 AC: 20 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.174 AC: 6895 AN: 39696

South Asian (SAS) AF: 0.00445 AC: 384 AN: 86246

European-Finnish (FIN) AF: 0.000216 AC: 10 AN: 46354

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.000720 AC: 801 AN: 1111892

Other (OTH) AF: 0.0110 AC: 666 AN: 60346

GnomAD4 genome AF: 0.00884 AC: 1346 AN: 152260 Hom.: 109 Cov.: 32 AF XY: 0.00954 AC XY: 710 AN XY: 74444

African (AFR) AF: 0.00491 AC: 204 AN: 41552

American (AMR) AF: 0.00164 AC: 25 AN: 15288

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

East Asian (EAS) AF: 0.191 AC: 987 AN: 5174

South Asian (SAS) AF: 0.00974 AC: 47 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68022

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00334 Hom.: 7

Bravo AF: 0.00975

Asia WGS AF: 0.0570 AC: 198 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.13
DANN	Benign	0.56
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs2285643; hg19: chr17-42330467; COSMIC: COSV52262665; COSMIC: COSV52262665;