rs945416

Variant names:

• chr1-16017907-G-A
• rs945416
• NM_014424.5:c.57C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_014424.5(HSPB7):​c.57C>T​(p.Ser19Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,613,376 control chromosomes in the GnomAD database, including 284,168 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.61 (28782 hom., cov: 35)
  • Exomes 𝑓: 0.59 (255386 hom.)
• Consequence: HSPB7 NM_014424.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.83
• Publications: 25 publications found

Genes affected

HSPB7 (HGNC:5249): (heat shock protein family B (small) member 7) This gene encodes a small heat shock family B member that can heterodimerize with similar heat shock proteins. Defects in this gene are associated with advanced heart failure. In addition, the encoded protein may be a tumor suppressor in the p53 pathway, with defects in this gene being associated with renal cell carcinoma. [provided by RefSeq, Mar 2017]

CLCNKA (HGNC:2026): (chloride voltage-gated channel Ka) This gene is a member of the CLC family of voltage-gated chloride channels. The encoded protein is predicted to have 12 transmembrane domains, and requires a beta subunit called barttin to form a functional channel. It is thought to function in salt reabsorption in the kidney and potassium recycling in the inner ear. The gene is highly similar to CLCNKB, which is located 10 kb downstream from this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CLCNKA Gene-Disease associations (from GenCC):

• Bartter disease type 4B

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics
• Bartter syndrome type 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014424.5. 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
	HSPB7	NM_014424.5	MANE Select	c.57C>T	p.Ser19Ser	synonymous	Exon 1 of 3	NP_055239.1	Q9UBY9-1
	HSPB7	NM_001349689.2		c.57C>T	p.Ser19Ser	synonymous	Exon 1 of 3	NP_001336618.1	Q9UBY9-2
	HSPB7	NM_001349683.2		c.57C>T	p.Ser19Ser	synonymous	Exon 1 of 3	NP_001336612.1	Q68DG0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB7	ENST00000311890.14	TSL:1 MANE Select	c.57C>T	p.Ser19Ser	synonymous	Exon 1 of 3	ENSP00000310111.9	Q9UBY9-1
	HSPB7	ENST00000487046.1	TSL:1	c.57C>T	p.Ser19Ser	synonymous	Exon 1 of 3	ENSP00000419477.1	Q9UBY9-2
	HSPB7	ENST00000406363.2	TSL:1	c.57C>T	p.Ser19Ser	synonymous	Exon 1 of 3	ENSP00000385472.2	Q68DG0

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92772 AN: 152084 Hom.: 28761 Cov.: 35

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.622

GnomAD2 exomes AF: 0.576 AC: 142795 AN: 248018 AF XY: 0.581

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.752

Gnomad FIN exome AF: 0.566

Gnomad NFE exome AF: 0.592

Gnomad OTH exome AF: 0.570

GnomAD4 exome AF: 0.589 AC: 860908 AN: 1461174 Hom.: 255386 Cov.: 50 AF XY: 0.590 AC XY: 428533 AN XY: 726860

African (AFR) AF: 0.699 AC: 23410 AN: 33470

American (AMR) AF: 0.403 AC: 18005 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 13456 AN: 26132

East Asian (EAS) AF: 0.728 AC: 28894 AN: 39692

South Asian (SAS) AF: 0.586 AC: 50507 AN: 86234

European-Finnish (FIN) AF: 0.565 AC: 30059 AN: 53220

Middle Eastern (MID) AF: 0.610 AC: 3515 AN: 5760

European-Non Finnish (NFE) AF: 0.591 AC: 656667 AN: 1111614

Other (OTH) AF: 0.603 AC: 36395 AN: 60360

GnomAD4 genome AF: 0.610 AC: 92833 AN: 152202 Hom.: 28782 Cov.: 35 AF XY: 0.604 AC XY: 44954 AN XY: 74400

African (AFR) AF: 0.688 AC: 28596 AN: 41552

American (AMR) AF: 0.489 AC: 7469 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1769 AN: 3466

East Asian (EAS) AF: 0.774 AC: 4005 AN: 5174

South Asian (SAS) AF: 0.596 AC: 2876 AN: 4824

European-Finnish (FIN) AF: 0.556 AC: 5895 AN: 10602

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.592 AC: 40249 AN: 67976

Other (OTH) AF: 0.621 AC: 1313 AN: 2116

Alfa AF: 0.590 Hom.: 25134

Bravo AF: 0.605

Asia WGS AF: 0.638 AC: 2219 AN: 3478

EpiCase AF: 0.588

EpiControl AF: 0.593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.3
DANN	Benign	0.92
PhyloP100		-1.8
PromoterAI		-0.14	Neutral
Mutation Taster		=96/4	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: rs945416; hg19: chr1-16344402; COSMIC: COSV58893094; COSMIC: COSV58893094;