1-62238305-G-A

Position:

• chr1-62238305-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181712.5(KANK4):​c.2960C>T​(p.Ala987Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 1,613,686 control chromosomes in the GnomAD database, including 1,051 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A987T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (63 hom., cov: 32)
  • Exomes 𝑓: 0.030 (988 hom.)
• Consequence: KANK4 NM_181712.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.231

Genes affected

KANK4 (HGNC:27263): (KN motif and ankyrin repeat domains 4) Predicted to be involved in negative regulation of actin filament polymerization. Located in cytosol and microtubule cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016061366).
• BP6: Variant 1-62238305-G-A is Benign according to our data. Variant chr1-62238305-G-A is described in ClinVar as [Benign]. Clinvar id is 1253133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANK4	NM_181712.5	c.2960C>T	p.Ala987Val	missense_variant	10/10	ENST00000371153.9	NP_859063.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANK4	ENST00000371153.9	c.2960C>T	p.Ala987Val	missense_variant	10/10	1	NM_181712.5	ENSP00000360195.4
KANK4	ENST00000354381.3	c.1076C>T	p.Ala359Val	missense_variant	9/9	2		ENSP00000346352.3
KANK4	ENST00000371150.5	c.1028C>T	p.Ala343Val	missense_variant	7/7	2		ENSP00000360192.1
KANK4	ENST00000317477.8	c.374C>T	p.Ala125Val	missense_variant	4/4	2		ENSP00000321161.4

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3837 AN: 152124 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00640

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.0951

Gnomad SAS AF: 0.0873

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0261

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0363 AC: 9112 AN: 251000 Hom.: 317 AF XY: 0.0396 AC XY: 5375 AN XY: 135688

Gnomad AFR exome AF: 0.00512

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.0381

Gnomad EAS exome AF: 0.0943

Gnomad SAS exome AF: 0.0880

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.0259

Gnomad OTH exome AF: 0.0328

GnomAD4 exome AF: 0.0302 AC: 44081 AN: 1461444 Hom.: 988 Cov.: 30 AF XY: 0.0320 AC XY: 23298 AN XY: 727020

Gnomad4 AFR exome AF: 0.00562

Gnomad4 AMR exome AF: 0.0209

Gnomad4 ASJ exome AF: 0.0380

Gnomad4 EAS exome AF: 0.0881

Gnomad4 SAS exome AF: 0.0848

Gnomad4 FIN exome AF: 0.0181

Gnomad4 NFE exome AF: 0.0251

Gnomad4 OTH exome AF: 0.0339

GnomAD4 genome AF: 0.0252 AC: 3832 AN: 152242 Hom.: 63 Cov.: 32 AF XY: 0.0265 AC XY: 1972 AN XY: 74438

Gnomad4 AFR AF: 0.00640

Gnomad4 AMR AF: 0.0286

Gnomad4 ASJ AF: 0.0427

Gnomad4 EAS AF: 0.0951

Gnomad4 SAS AF: 0.0870

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.0261

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0281 Hom.: 132

Bravo AF: 0.0241

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0272 AC: 234

ExAC AF: 0.0357 AC: 4338

Asia WGS AF: 0.0890 AC: 310 AN: 3478

EpiCase AF: 0.0278

EpiControl AF: 0.0325

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.010	T;T;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.21	T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.23	N;N;N;N
REVEL	Benign	0.0090
Sift	Benign	0.36	T;T;T;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.11, 0.31	.;B;.;B
Vest4		0.069
MPC		0.11
ClinPred		0.013	T
GERP RS		3.1
Varity_R		0.025
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs34591898; hg19: chr1-62703977;