NM_001349682.2:c.337-278G>C

Variant names:

• chr1-16018130-C-G
• rs945417
• NM_001349682.2:c.337-278G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001349682.2(HSPB7):​c.337-278G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,546,386 control chromosomes in the GnomAD database, including 251,782 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 0.60 (28043 hom., cov: 33)
  • Exomes 𝑓: 0.56 (223739 hom.)
• Consequence: HSPB7 NM_001349682.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.795
• Publications: 15 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.017).
• 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_001349682.2. 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_001349682.2		c.337-278G>C		intron	N/A	NP_001336611.1	Q8N241
	HSPB7	NM_014424.5	MANE Select	c.-167G>C		upstream_gene	N/A	NP_055239.1	Q9UBY9-1
	HSPB7	NM_001349689.2		c.-167G>C		upstream_gene	N/A	NP_001336618.1	Q9UBY9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB7	ENST00000375718.4	TSL:2	c.337-278G>C		intron	N/A	ENSP00000364870.4	Q8N241
	HSPB7	ENST00000956995.1		c.-38-129G>C		intron	N/A	ENSP00000627054.1
	HSPB7	ENST00000861615.1		c.-38-129G>C		intron	N/A	ENSP00000531674.1

Frequencies

GnomAD3 genomes AF: 0.599 AC: 91041 AN: 151978 Hom.: 28017 Cov.: 33

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.608

GnomAD2 exomes AF: 0.546 AC: 82419 AN: 151064 AF XY: 0.551

Gnomad AFR exome AF: 0.722

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.758

Gnomad FIN exome AF: 0.524

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.545

GnomAD4 exome AF: 0.564 AC: 786154 AN: 1394290 Hom.: 223739 Cov.: 57 AF XY: 0.564 AC XY: 387679 AN XY: 687786

African (AFR) AF: 0.731 AC: 23029 AN: 31500

American (AMR) AF: 0.405 AC: 14394 AN: 35582

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 11432 AN: 25050

East Asian (EAS) AF: 0.730 AC: 25943 AN: 35540

South Asian (SAS) AF: 0.558 AC: 43793 AN: 78504

European-Finnish (FIN) AF: 0.528 AC: 25277 AN: 47910

Middle Eastern (MID) AF: 0.560 AC: 3108 AN: 5550

European-Non Finnish (NFE) AF: 0.562 AC: 605739 AN: 1076950

Other (OTH) AF: 0.579 AC: 33439 AN: 57704

GnomAD4 genome AF: 0.599 AC: 91107 AN: 152096 Hom.: 28043 Cov.: 33 AF XY: 0.592 AC XY: 44046 AN XY: 74360

African (AFR) AF: 0.719 AC: 29840 AN: 41494

American (AMR) AF: 0.476 AC: 7274 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1556 AN: 3472

East Asian (EAS) AF: 0.774 AC: 3994 AN: 5160

South Asian (SAS) AF: 0.577 AC: 2782 AN: 4822

European-Finnish (FIN) AF: 0.519 AC: 5498 AN: 10590

Middle Eastern (MID) AF: 0.640 AC: 187 AN: 292

European-Non Finnish (NFE) AF: 0.564 AC: 38344 AN: 67952

Other (OTH) AF: 0.606 AC: 1280 AN: 2112

Alfa AF: 0.562 Hom.: 7863

Bravo AF: 0.598

Asia WGS AF: 0.631 AC: 2195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.93
PhyloP100		0.80
PromoterAI		-0.037	Neutral
Mutation Taster		=300/0	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: rs945417; hg19: chr1-16344625; COSMIC: COSV58890268; COSMIC: COSV58890268;